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Illustration of the digestive system: Image reprinted from “Your Digestive System and How It Works.” U.S. Department of Health and Human Services. National Institutes of Health, National Institute of Diabetes and Digestive and Diseases. NIH Publication No. 08-2681, April 2008.

Inset images: Top image and third image down—Richard Nowitz for NIDDK; second image down— Used with permission of the NIDDK Weight-Control Information Network; Bottom image—Randy Faris/Corbis. Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases

U.S. Department of Health and Human Services National Institutes of Health

NIH Publication No. 08-6514 March 2009

TABLE OF CONTENTS

Executive Summary 1

Introduction 13

TOPIC-SPECIFIC CHAPTERS

Research on the Basic of the Digestive System 25

Functional Gastrointestinal Disorders and Motility Disorders 51

Infections of the 69

Cancers of the Digestive System 81

Inflammatory Bowel Diseases 95

Intestinal Failure and Regeneration, Nutritional Disorders and Support, Surgically Modified , and Transplantation 107

Diseases of the Oropharynx and 117

Diseases of the and 129

Diseases of the Colon and 145

Diseases of the 159

Diseases of the and Biliary System 169

Bioengineering, Biotechnology, and Imaging 187

Conclusion: Common Themes and Steps for Implementation 195

APPENDICES

Appendix 1: Summary List of Recommended Research Goals and Common Themes 207

Appendix 2: Rosters of the National Commission on Digestive Diseases and Its 214 Working Groups

Appendix 3: References for Statistical and Epidemiologic Data 220

Appendix 4: Abbreviations and Acronyms 221

Index 226

Acknowledgements 238  Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Executive Summary

Burden of Digestive Diseases in Health and Human Services, and Education, the United States and Related Agencies. The Commission was tasked with reviewing the state of the science The digestive system can be affected by a in digestive diseases research and developing a wide diversity of acute and chronic diseases or 10-year plan for digestive diseases research that conditions that, collectively, place a substantial is consistent with the NIH mission and aimed burden on the U.S. healthcare system. At least at improving the health of the Nation through 60-70 million Americans are affected each year research. The Commission was comprised of by digestive diseases at a cost that exceeds $100 16 members, including academic researchers, billion in direct medical expenses. Annually, medical professionals, and patient advocates, about 10 percent of hospitalizations and 15 who were appointed by the NIH Director after percent of in-patient procedures are a public nomination process. In addition, 22 attributed to the treatment of digestive diseases. representatives of NIH Institutes and Centers, An additional 105 million visits to doctors’ offices as well as other Federal agencies involved in related to digestive diseases occur each year. digestive diseases research, served as ex officio These diseases are associated with significant members of the Commission. Stephen P. James, mortality, morbidity, and loss of quality of life, M.D., Director of the Division of Digestive and they frequently impact patients’ ability Diseases and Nutrition of the National Institute to work or engage in everyday activities. More of Diabetes and Digestive and Kidney Diseases than $44 billion in indirect costs from disability (NIDDK), NIH, chaired the Commission. Working and mortality are associated with digestive groups composed of experts in diverse areas of diseases each year. Digestive diseases in digestive diseases research were formed to aid general can affect individuals of any age, race the Commission in identifying major scientific or ethnicity, gender, or socioeconomic status, advances and formulating high-priority although some diseases disproportionately affect research goals. certain populations. All of these factors provide opportunities and challenges for the National This report, entitled Opportunities and Institutes of Health (NIH) as it develops and Challenges in Digestive Diseases Research: supports research programs aimed, ultimately, Recommendations of the National Commission at reducing the significant burden on Digestive Diseases, presents the Commission’s of digestive diseases. long-range plan for digestive diseases research. The Commission offers recommendations in many broad areas of scientific inquiry of National Commission on relevance to digestive diseases, including Digestive Diseases fundamental biology of the digestive system, as well as disease-oriented research topics, such as: The National Commission on Digestive Diseases epidemiology; environmental factors; genetics; was chartered by Elias A. Zerhouni, M.D., mechanisms; diagnosis; causes; treatments; Director of the NIH, on July 26, 2005, in response behavioral, social, and psychological factors; to congressional report language accompanying health disparities; prevention; and cures. the FY 2005 appropriations bills in the House The Commission developed specific research and Senate for the Departments of Labor, goals in each of the following 12 scientific topic

Executive Summary  areas: research on the basic biology of the laboratories. To aid in the development of the digestive system; functional gastrointestinal recommendations in this research plan, lists of disorders and motility disorders; grants and other awards comprising the NIH of the gastrointestinal tract; of the portfolio for digestive diseases were provided to digestive system; inflammatory bowel diseases; members of the Commission and to each intestinal failure and regeneration, nutritional working group. disorders and support, surgically modified gut, and transplantation; diseases of the oropharynx In addition to the direct funding of digestive and esophagus; diseases of the stomach and diseases research, the NIH coordinates small intestine; diseases of the colon and research programs within the agency and rectum; diseases of the pancreas; diseases of the with other Federal agencies with an interest liver and biliary system; and bioengineering, in digestive diseases through the Digestive biotechnology, and imaging. In addition, the Diseases Interagency Coordinating Committee Commission identified a set of high-priority, (DDICC). The DDICC brings together common themes for which coordinated research representatives from multiple NIH Institutes planning efforts would accelerate progress and Centers that fund digestive diseases across the digestive disease research field by research, as well as from other agencies, fostering the development and utilization of including the Agency for Healthcare Research state-of-the-science technologies, tools, and and Quality, the Food and Drug Administration, resources to increase fundamental knowledge, the Department of Defense, the Centers improve translation of research advances into for Disease Control and Prevention, the applications for human diseases, and ensure a Department of Veterans Affairs, the Health robust pipeline of talented researchers focused on Resources and Services Administration, the challenges of digestive diseases. Collectively, and the Department of Agriculture. The the Commission’s recommendations will provide NIH also promotes communication and scientific direction for theNIH and all parties collaboration within the digestive diseases engaged in digestive diseases research as they research community through the support of address opportunities and priorities in digestive conferences and workshops on relevant topics. diseases research over the next decade. Finally, the NIDDK-led National Digestive Diseases Information Clearinghouse provides informational materials and other resources NIH support for digestive with the goal of increasing knowledge and diseases research understanding of digestive diseases within the healthcare community and the general public. NIH Funding and Coordination of Digestive Diseases Research Advances in Digestive Diseases Research

Twenty NIH Institutes, Centers, and Offices Digestive diseases research supported by the support digestive diseases research on a variety NIH and other public and private organizations of topics with a total expenditure of more than has resulted in many breakthrough discoveries $1.2 billion in FY 2007. The NIH research that have advanced our understanding of portfolio encompasses basic, translational, digestive system biology and function, as well as and clinical research and training on the improved the health and quality of life of many digestive system for normal states and disease people with digestive diseases. conditions and supports extramural researchers and institutions, as well as intramural

 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Examples of research advances include: ß Advances in surgical techniques to lengthen the intestine have enhanced the management ß Molecular signaling pathways have been of and children with refractory short uncovered in intestinal crypt progenitor cells bowel syndrome. Intestinal lengthening that are responsible for continual regeneration procedures such as serial transverse of the intestinal lining. Understanding these enteroplasty and the Bianchi procedure lead pathways gives researchers new insights to improved intestinal function and nutrient into the genetic basis of colorectal , as absorption in these patients. well as processes such as normal intestinal development and . ß Risk factors for Barrett’s esophagus are being better defined. Researchers are finding ß Researchers have discovered that neural that this disease is not as closely associated stem cells persist in the gut after birth. with chronic symptoms as once Stem cells from other sources also may have thought. and central adiposity, in potential for generating replacement particular, appear to be important risk factors in the gastrointestinal (GI) tract. Stem for Barrett’s esophagus. New high-resolution research holds promise for future clinical imaging techniques are being developed that applications in digestive disease . have the potential to identify early cancers in these patients. ß The development and licensing of two vaccines is an important advance ß The identification of the microbe Helicobacter in the prevention of rotavirus infections, the pylori as a cause of peptic disease leading cause of severe diarrheal disease and quickly led to the use of to dehydration in infants and young children. effectively treat . Likewise, research on Similarly, research to develop and test vaccines the role of cyclooxygenases in non-steroidal for hookworm, , and amebiasis anti-inflammatory drug (NSAID)-induced has the potential to make a global impact on GI injury led to the development of new the prevention of these infectious diseases. strategies to reduce the GI toxicity associated with some NSAIDs and prevent ulcer ß New endoscopic imaging techniques have in high-risk patients. improved detection of a variety of cancers in high-risk patients, such as squamous ß Researchers using modern genetic techniques , pancreatic ductal and have discovered that the human gut other cancers, and cancers of the GI . microflora are far more complex than once Research to discover genetic risk factors thought. The of healthy subjects contain for GI cancers has enabled better risk thousands of bacterial species, most of which assessment of individuals with a family are novel, uncultivated . Research history of these cancers. to characterize the relative abundance of different microbes in obese and lean ß Progress has been made in identifying genes individuals could lead to the development of that increase susceptibility to inflammatory techniques to manipulate the microflora as a bowel diseases. By studying the mechanistic means to alter body weight. processes associated with these genes, researchers can develop better models of ß Progress in technology disease risk, improve methods to predict the has dramatically improved the ability to course of disease, and develop more targeted visualize changes in pancreatic structure and for inflammatory bowel diseases. allowed for the possibility of early diagnosis

Executive Summary  of chronic . This technique also plan. In addition, working groups comprising provides clinicians with the means to obtain additional experts in each scientific topic area tissue for histologic diagnosis of chronic were convened to advise the Commission on the pancreatitis without the need for surgical current state of the science in digestive diseases resection of the pancreas. research and to identify high-priority research goals to be addressed over the next decade. A ß The development of an effective vaccine near-final draft of the research plan was posted against the that causes acute online for public comment before being approved B and its use in successful by the Commission and submitted to the NIH programs represent a major advance that has Director and the Congress. contributed to a significant reduction in the incidence of this disease in the U.S. Moreover, The Commission’s recommendations are the introduction of tests that can detect the organized into 12 scientific topic areas that presence of and C in categorize digestive diseases by common has nearly eliminated their transmission etiology, mechanism, affected system, through blood donation. or other considerations. For each topic area, the Commission has provided: an overview ß Development of the video capsule endoscope of common diseases or conditions; a review of has revolutionized imaging of the small bowel significant research advances; a description of mucosa and facilitated the evaluation of high-impact, forward-looking, science-based common disorders, such as Crohn’s disease, research goals; and a discussion of major idiopathic inflammatory diseases of the barriers to research progress and steps to small bowel, and malignancy. Occult bleeding overcome those challenges. The goals, which from the small bowel may now be identified, are not prioritized, each include a list of specific addressing a longstanding clinical dilemma objectives that represent more discrete, shorter- prior to this technology. term steps toward achieving the overall goal. Although it was not possible to explicitly address every digestive disease that affects the human rEcommEndationS oF tHE population, the Commission noted that many of national commiSSion on the research recommendations are expected to digEStivE diSEaSES have a broad impact on diseases of the digestive system, including those not explicitly mentioned. Development and Organization of the In addition, it should be noted that diseases of Long-Range Research Plan of the National the oral cavity and general aspects of nutrition Commission on Digestive Diseases research (not related to digestive diseases and their treatment) were not considered in the This research plan describing opportunities development of this research plan. and challenges in digestive diseases research was developed by the Commission through a High-Impact Goals for Digestive collaborative, transparent process that involved Diseases Research multiple opportunities for engagement of the research, clinical, and patient communities With the assistance of its working groups, the with an interest in digestive diseases. The full Commission identified high-priority research Commission held five public meetings throughout goals that, if pursued over the next decade, have the duration of its charter to develop and discuss the potential to expand our understanding of the structure and content of the research digestive system biology and accelerate the

 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases development of new strategies for prevention, ß Functional Gastrointestinal Disorders diagnosis, treatment, and cure of digestive and Motility Disorders diseases. These major research goals are Functional GI disorders and motility summarized below: disorders, such as , functional dyspepsia, and gastroesophageal ß Research on the Basic Biology of the reflux disease, take a significant toll on the Digestive System health and well-being of many Americans. The Commission proposes multiple The Commission offers several research research goals to achieve the overarching goals designed to improve our understanding mission of understanding the basic biologic of normal motility and secretory activities underpinnings of the structurally and of the GI tract, discover the physiologic functionally complex digestive system. changes that lead to disease, and develop Developing new technologies to isolate, more effective therapies to prevent, treat, characterize, cultivate, and manipulate stem or reverse these disorders. Research efforts cells of the digestive system may provide new are needed on the numerous systems and approaches to understand the pathogenesis processes that may be impaired in functional and develop new therapies for digestive GI and motility disorders, including brain-gut diseases. Uncovering the mechanisms that interactions, the enteric , control development and differentiation interstitial cells of Cajal and of the digestive tract before birth and in cells, and sensory mechanisms, the neonatal life could generate new insights gut mucosa and musculature, the intestinal for regenerative therapies to treat digestive microflora, and immune andinflammatory cancers and other diseases, as well as provide responses. It is important to define how new insights into disease pathogenesis. factors such as genetic differences, age, sex, Studying the fundamental mechanisms and gender influence a person’s susceptibility of could point to new strategies to these disorders. Many individuals with for treating disorders of nutrient and fluid diabetes develop GI motility disorders, such absorption, secretion, and . The as and . As the links the digestive rate of diabetes continues to rise in the U.S., system and the brain and controls motility research on how diabetes affects the GI within the GI tract. Research on the function tract is increasingly important. Ultimately, and organization of the enteric nervous research to discover the basic mechanisms system will enable a better understanding of of disease must be translated into new gut motility in digestive health and disease. technologies, pharmacological therapies, The intestinal microflora are essential to and behavioral strategies to effectively treat normal digestive function; studying the all patients afflicted with functional GI and composition and activity of commensal motility disorders. organisms in healthy individuals could reveal important links between alterations ß Infections of the Gastrointestinal Tract in the microflora and human disease. Finally, GI infections can be caused by many types the mucosal is a critical of microbes, including , viruses, component of the body’s defenses against protozoa, and helminths. The Commission disease. Understanding the mechanisms by recommends research goals that are focused which this system operates could lead to new on identifying disease-causing microbes, vaccination strategies or other approaches understanding what distinguishes those to prevent or treat infectious diseases that organisms from the normal microflora of the affect the digestive system. human GI tract, and using that knowledge

Executive Summary  to develop safe, effective therapies to prevent esophageal cancer, , gastric and treat intestinal infections. Developing cancer, , or certain rare GI new, more efficient diagnostic methods to cancers. Together, these research goals aim to identify specific organisms is critical for improve the health and lives of people at risk rapid treatment and for understanding the for or living with digestive cancers. epidemiology of infectious disease outbreaks. Research is needed to develop better ß Inflammatory Bowel Diseases treatments, including vaccines, that address Inflammatory bowel diseases IBD)( are a both the infectious agents themselves, diverse group of digestive tract disorders of as well as the long-term effects of GI often unknown origin and complex disease in the gut and other organ systems management. Given the potentially severe throughout the body. The human GI tract is impact of these diseases on patients’ quality colonized from birth with microorganisms of life, cancer risk, growth and development in that are essential for normal growth and childhood and adolescence, and other serious digestive function. Research on the nature health issues, the Commission proposes and function of the human microflora could a set of research goals that are intended suggest strategies to manipulate these to accelerate progress on understanding, beneficial microbes to combat pathogenic preventing, and effectively managing these organisms. Collectively, achievement of diseases in all patients. An urgent research these goals has the potential to reduce the goal is the development of objective criteria public health burden of infectious diseases for IBD diagnosis and risk evaluation, based in the U.S. and globally. on phenotypic and genetic characteristics, which would enable reliable subclassification ß Cancers of the Digestive System of patients and their diverse constellations Recognizing the substantial public health of symptoms. Such validated criteria could impact of digestive system cancers, the facilitate clinical evaluation and disease Commission recommends several research management approaches that are tailored goals targeted at improving the detection, to individual needs and that improve prevention, and treatment of these diseases. the efficiency of clinical trials to test new Research is needed to develop more efficient therapies. Strategies to prevent or control screening tools to predict and detect IBD that could be tested include modulation digestive tract cancers and pre-malignant of the intestinal microflora or themucosal conditions that frequently progress to immune system. These and other therapeutic cancer. These efforts would be bolstered by approaches are targeted at maintaining identifying health disparities that influence the health of the intestinal mucosa and an individual’s susceptibility to digestive stimulating regeneration and repair in system cancers or their response to treatment. patients with IBD. In addition, finding ways to Understanding the underlying mechanisms alleviate the unique developmental challenges common to all digestive cancers and faced by children with IBD is a particularly identifying biomarkers to detect disease or important goal in this research area. predict response to treatment would accelerate the search for safe, effective therapies. In ß Intestinal Failure and Regeneration, order to develop targeted strategies for cancer Nutritional Disorders and Support, detection, prevention, and treatment, it is Surgically Modified Gut, and critical that researchers identify the genetic Transplantation risk factors that predispose an individual to Loss of intestinal function can occur through a specific form of digestivecancer, such as surgical removal of tissue or diseases that

 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases impair digestion or cause tissue death. The Barrett’s esophagus and esophageal cancer. Commission recommends research goals that, Thus, research is needed to uncover the if pursued, would increase understanding risk factors and mechanisms of disease of the natural mechanisms of growth, progression in order to develop more effective differentiation, and adaptation in the GI prevention and treatment strategies. The tract and use that information to better emergence of eosinophilic and treat patients with GI diseases. Research is other inflammatory diseases of theesophagus needed on the development of new treatment over the last decade highlights the need for strategies for and research to define the clinical course of these intestinal failure, including innovative poorly understood diseases and design rational approaches to optimizing intestinal therapies to reverse them. Progress toward transplantation and post-transplant survival. these research goals will help to reduce the GI tract , including bariatric significant economic toll that these diseases, surgeries for weight loss, are frequently particularly GERD, take on individuals and associated with nutritional or hormonal the U.S. healthcare system. complications. An important research focus is improving nutritional support for surgical ß Diseases of the Stomach and Small patients and others with digestive diseases Intestine who rely on parenteral or enteral nutrition to The impact of research on diseases of the sustain life, including premature infants with stomach and small intestine is epitomized necrotizing . Achieving these by the discovery of research goals would markedly enhance the and its role in peptic ulcers, which quickly quality of life and health of many patients revolutionized the treatment of many, with digestive diseases or injury who are though not all, patients with peptic ulcers. unable to properly absorb nutrients through To capitalize on this and other advances, the their GI tract. Commission proposes several research goals to improve understanding of the diverse ß Diseases of the Oropharynx and diseases that affect the stomach and small Esophagus intestine and to accelerate development of Because normal functioning of the oropharynx effective therapies. can and esophagus can be compromised by a be triggered by multiple causes in addition wide spectrum of diseases, the Commission to H. pylori. Research efforts are needed suggests a number of research goals that to understand the mechanisms of ulcer address the diverse etiologies and potential formation and mucosal injury and to develop treatments for these disorders. Research new approaches to prevention and treatment to understand the neuromuscular biology of ulcers, especially those associated with non- of the oropharynx and esophagus is critical steroidal anti-inflammatory drugs. Developing to developing therapies for conditions like effective treatments for and other disorders brought on by stroke, maldigestive/malabsorptive diseases requires premature birth, non-erosive reflux disease, better understanding of the fundamental and other motility disorders that affect this mechanisms of water, nutrient, and portion of the GI tract. Similarly, more studies transport in the intestine. Research on are needed to identify better therapeutic celiac disease and other autoimmune and targets for gastroesophageal reflux disease allergic diseases that affect the digestive (GERD), among the most common diagnoses tract is needed to uncover the genetic and for a digestive disorder in the U.S. GERD environmental triggers of such conditions is also associated with increased risk for and to improve methods of diagnosis and

Executive Summary  treatment. Finally, focused research efforts are more than 1 million Americans each year. critical for diseases of unknown origin, such The Commission recommends a series of as necrotizing enterocolitis and eosinophilic research goals that are focused on the most GI diseases, for which few effective treatment prevalent of these disorders—acute and options are available. and their sequelae. Pancreatitis can be triggered by many ß Diseases of the Colon and Rectum possible causes, including , alcohol The colon and rectum are susceptible to a abuse, certain , , variety of diseases and conditions that can and diseases such as cystic fibrosis, or it may impair their primary functions of maintaining be of unknown etiology. Research is needed to water balance and eliminating wastes. The identify the biologic and genetic factors that Commission’s proposed research goals are increase a person’s susceptibility to acute aimed at understanding mechanisms of pancreatitis and/or the transition to chronic colonic injury, repair, and function so that disease. The development of innovative prevention and treatment strategies for these diagnostic, preventive, and therapeutic disorders can be optimized. Key topics for approaches to pancreatitis has the potential research on colonic diseases are elucidating to reduce the burden of this disease in both the role and composition of the gut microflora children and adults. Equally important is and manipulating this microbial community the need to understand the mechanisms to restore health. Studies are also needed to of pancreatic pain, a highly prevalent establish the basis for structural defects like of all forms of pancreatitis that diverticular disease and vascular disorders, is difficult to treat and severely erodes the such as colonic ischemia and angioectasias. quality of life of patients with pancreatic Better means of detection and treatment disease. Research to understand the risk would improve the health and quality of life of factors for and mechanisms of progression to elderly individuals who are most affected by pancreatic cancer is particularly critical for these conditions. Research is urgently needed patients who develop pancreatitis at a young on anorectal disorders, including anal fistulas, age and are, therefore, at a corresponding , and , which increased lifetime risk for pancreatic cancer. lack a firm evidence base concerning the causes and effective management strategies ß Diseases of the Liver and Biliary System for these common, but poorly studied, Major research goals relating to diseases of conditions. Research on ways to prevent the liver and biliary system were set forth in and treat radiation injury of the colon would the trans-NIH Action Plan for alleviate this treatment-induced complication Research, which was released in 2004. Taking of pelvic cancer therapy. Finally, that effort into consideration, the Commission can be fatal if undiagnosed and untreated. proposes research goals that are intended to Research on the risk factors for onset and complement and reinforce the comprehensive progression of appendicitis would further recommendations made in the Action Plan. reduce the burden of this condition, especially Understanding normal liver and biliary in children. function and development will provide a solid foundation for new approaches to detect, ß Diseases of the Pancreas prevent, and treat liver and biliary diseases. The exocrine pancreas, which produces Although the burden of some forms of viral and secretes multiple necessary hepatitis has decreased in recent years due for digestive function, is vulnerable to a to efforts such as the development of vaccines variety of disorders that, collectively, affect and antiviral therapies, more work is needed

 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases to find safe, effective means for prevention will need to be developed in order to realize and treatment of all forms of acute and the potential of promising tissue engineering chronic , as well as human approaches. The development of advanced virus HIV)-associated( imaging technologies and interactive liver disease. Hepatic steatosis (fatty liver simulators that allow to plan and disease) is an increasingly common form of practice procedures using patient-specific liver disease in the U.S. Research to discover images would reduce the risk of trauma to the basic mechanisms underlying steatosis healthy tissue during treatment. Collectively, will point to new therapeutic strategies. these research goals will lead to innovative Similarly, research is needed to uncover technologies that have the potential to the genetic bases and fundamental cellular significantly improve patient outcomes mechanisms of a range of disorders, including and enhance treatment efficacy for many drug-induced liver disease, autoimmune digestive diseases. diseases of the liver, childhood syndromes and other hereditary liver diseases, , liver cancers, and gallstones. More knowledge of all conclusion of these conditions will accelerate the search for new means of prevention, diagnosis, and Pressing Need for a Substantial Research treatment, such as improved procedures for Effort in Digestive Diseases , to reduce the burden of liver and biliary diseases in the U.S. Disorders of the digestive system affect the majority of the U.S. population at some time ß Bioengineering, Biotechnology, throughout life. Many decades of NIH-funded and Imaging research in digestive diseases have led to a The luminal structure of the gastrointestinal detailed understanding of the digestive system, tract and the inherent regenerative the causes of many diseases, and improved capacities of many cell types within the treatments that are now the standard of care. organs of the digestive system afford Examples of research advances that have significant opportunities for the development reduced the burden of digestive diseases include: of innovative technologies and approaches the discovery of H. pylori as a major cause of to the diagnosis and treatment of digestive ulcer disease; discovery of the multiple forms diseases. The Commission recommends of viral hepatitis and development of curative several research goals that are intended treatments and preventive vaccines; and to capitalize on emerging technologies implementation of effective screening programs and facilitate medical and surgical care of to prevent colorectal cancer. digestive disease patients. Ready access to much of the digestive tract is permitted by Nonetheless, the current solutions for the endoscopic or minimal access approaches prevention, diagnosis, or treatment of digestive for or resection of tissue. Research is diseases are often imperfect and costly. In needed to evaluate the risks and benefits of addition, progress on many digestive diseases, such procedures compared to conventional such as the functional GI disorders, pancreatitis, surgical techniques. Advances in stem cell and others, has occurred at a much slower rate. biology and regenerative could be Conditions associated with the rising prevalence applied to foster the repair and regeneration of obesity, such as non-alcoholic , of diseased tissue within the digestive are likely to increase the burden of digestive system. Innovative scaffolds to guide the diseases in the U.S. The Director of the NIH, growth of complex digestive organ structures recognizing both the great burden of digestive

Executive Summary  diseases in the U.S. and the diversity and on the development and application of new complexity of basic, translational, and clinical technologies, including development of animal research approaches that could be brought to models, high-throughput DNA sequencing, bear on the problem, chartered the National proteomics, high-resolution imaging, and Commission on Digestive Diseases to make many others. recommendations to the NIH for future research on digestive diseases. ß Theme 2: Translate fundamental new knowledge for the direct benefit Common Themes of individuals. Increased efforts in translational research will be needed to While developing its recommendations for achieve the long-term goals of this research goals and objectives within the 12 topic areas, plan and move the knowledge developed the Commission noted recurring themes that through basic research into routine clinical transcend much of digestive disesases research. practice. Translational research would The Commission notes that strong support by be facilitated by collaborative efforts to NIH and other participants in the research better define patient phenotypes and to process for coordinated research planning identify biomarkers that can be used to efforts to address these common themes will predict disease or response to treatment. be critical to the continued success of digestive Epidemiologic research through patient diseases research. registries and natural history studies would generate new, testable hypotheses and aid ß Theme 1: Increase the fundamental in the design of clinical trials. Academia- knowledge base for understanding industry partnerships should be encouraged health and digestive diseases. Basic and to foster the development and validation translational research provides essential of new technologies for clinical research knowledge about the normal, healthy digestive and treatment. Translation of research system and how it is perturbed in disease. from the bench to bedside requires both the Research to elucidate the molecular basis implementation of adequately powered, of biologic and pathologic processes in the randomized clinical trials as well as efforts, digestive system is needed to form the basis such as education and awareness campaigns, for discovery of new drugs to intervene in to ensure that the results of successful trials disease processes. Identifying genes and are readily adopted in clinical practice. All gene-environment interactions that influence of these efforts rely on the formation and susceptibility to disease will lead to better support of teams of individuals with the understanding of mechanisms of disease and diverse expertise needed to effectively design, new strategies for diagnosis and personalized implement, and evaluate clinical research medicine. As researchers increasingly studies and clinical trials. appreciate the complexity of the microflora populating the human gut, new technologies ß Theme 3: Develop research resources will be needed to fully characterize this and infrastructure. New technologies microbial community and understand its role have revolutionized biomedical research, in health and disease. Research in fields such including the digestive diseases research as , developmental biology, and field. Often, these technologies are expensive stem cell biology are needed to gain insights and require access to well-characterized into the pathogenesis of many digestive specimens and data, as well as highly-trained diseases. Finally, continued progress in the research expertise. Developing resources digestive diseases research field depends to increase access to patient biosamples or

10 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases data is especially critical to promote research to prevent, treat, or cure a diverse group of on rare digestive diseases for which few conditions that affect the GI tract, liver, biliary patients are seen by individual investigators system, and exocrine pancreas. The goals, or at specific medical centers. Equally objectives, and challenges identified in this important is the creation and dissemination research plan represent a formidable challenge of a variety of animal models for basic and to all parties in the research process. It is hoped preclinical research on digestive diseases. that these partners will use this research plan At all stages of research, support for diverse, as a scientific guidepost to identify promising multidisciplinary teams of scientists is future research opportunities to address the crucial for the optimal development and burden of digestive disease. The NIH should application of new technologies and resources continue to solicit broad stakeholder input as for digestive diseases research. it oversees implementation of this long-range research plan for digestive diseases through ß Theme 4: Maintain a pipeline of the activities of coordinating bodies, such as the research investigators for the future. Digestive Diseases Interagency Coordinating In the long-term, continuing progress Committee and other entities. in digestive diseases research relies on attracting the best and brightest new A large number of individual steps will need investigators and supporting their efforts to be taken by the many partners engaged in to launch sustainable, productive research digestive diseases research over the 10-year careers. A variety of approaches are needed to time horizon of this research plan to achieve foster new investigators, including research its many complex goals and objectives. The training, fellowship, and career development members of the Commission recognize that opportunities, as well as incentives for more research progress often occurs in a “bottom up” established investigators to serve as mentors. fashion, not only rapidly outstripping the best Higher paylines for new investigators laid efforts of scientific planners, but also as applying for an R01-equivalent grant and a result of the innovative ideas and initiative loan repayment programs are important of individual scientists and research teams. mechanisms for retaining researchers at However, it is also clear that certain types of a vulnerable stage in their careers. Efforts research projects and programs, as well as should be made to encourage the entry of specific resources and infrastructure, require under-represented minorities into digestive central, “top-down” organization led by funding diseases research. Finally, research training institutions with the flexibility to apply optimal and education opportunities could be mechanisms to address promising research developed to train researchers in the use of directions as they arise. Thus, the Commission complex new technologies and to encourage recommends that the NIH maintain an PhD scientists to pursue translational and approach focused on the goals set forth in this clinical research on digestive diseases. research plan that includes a substantial and balanced portfolio of programs with three Steps for Implementation of Research Goals major elements: strong support of investigator- initiated research project grants; initiatives This research plan of the National Commission designed to strategically address special needs on Digestive Diseases describes numerous, far- and opportunities; and programs that ensure ranging, long-term goals and specific objectives a pipeline of new investigators to meet the to improve the health of the Nation through continuing needs of digestive diseases research basic, translational, and clinical research that in the future. will lead to the discovery of improved ways

Executive Summary 11

Introduction

DIGESTIVE DISEASES: OVERVIEW AND cured. Dysregulation of the immune system PUBLIC HEALTH BURDEN or inflammation can lead toceliac disease, Crohn’s disease, , or The digestive system is a complex, multi-organ related conditions. Similarly, disorders such structure that performs many vital functions, as Hirschsprung’s disease, irritable bowel including nutrient absorption and waste syndrome, and intestinal pseudoobstruction disposal. The tubular gastrointestinal (GI) are associated with dysfunction of the nervous tract includes the , esophagus, stomach, system or musculature of the GI tract. Digestive small intestine, colon or , rectum, diseases can be caused by infectious agents, and . The luminal surface along much of such as viral hepatitis or ulcers due to infection this tract is lined with cells that either secrete with Helicobacter pylori, or may be treatment- substances that aid in breaking down ingested related, such as radiation , short bowel food or that absorb nutrients and water into syndrome due to surgical resection of the gut, the bloodstream for distribution throughout or ulcers caused by the use of non-steroidal the body. The layers of muscles and associated anti-inflammatory drugs (NSAIDs). Cancer that surround the lumen propel food can develop along any part of the luminal gut and waste through the system for eventual or in the solid organs of the digestive system. elimination. Even in healthy individuals, the Conditions named in this section are only a few digestive tract is colonized by thousands of examples of the many diseases that impact the microbial species that play a role in normal digestive system. digestion and help maintain proper nutrition. Solid organs of the also The burden of digestive diseases on the U.S. contribute to the digestive process. The pancreas healthcare system is substantial. At least 60 to secretes enzymes into the small intestine to help 70 million Americans are affected each year by break down , , and . digestive diseases at a cost that exceeds $100 The liver and biliary system ( ducts, billion in direct medical costs. Annually, about ) secrete bile into the small intestine 14 million hospitalizations—10 percent of the to aid in the digestion of fat. In addition, the total—and 15 percent of all in-patient hospital liver processes nutrients absorbed by the small procedures are attributed to treatment for intestine into forms that can be used by the body digestive diseases. In addition, 105 million visits and detoxifies potentially harmful substances. to doctors’ offices occur each year for digestive diseases, frequently in response to symptoms such Diseases of the digestive system comprise an as , diarrhea, , or . exceptionally diverse array of disorders and Prescription drugs for the treatment of certain conditions. Conditions such as acute digestive diseases such as gastroesophageal reflux pancreatitis, appendicitis, and foodborne disease rank among the most commonly used gastrointestinal infections develop suddenly pharmaceutical drugs in the U.S. and usually resolve in a relatively short time. Other disorders, including inflammatory bowel On a personal level, digestive diseases are diseases and non-alcoholic steatohepatitis, associated with significant mortality, morbidity, are chronic and may be controlled, but not yet and loss of quality of life. Digestive diseases,

Introduction 13 including cancer, are named as a primary cause and public health. The cumulative efforts of of death for approximately 236,000 people scientists working to uncover the fundamental in the U.S. each year. Moreover, digestive principles of digestive health and disease diseases can severely affect patients’ quality have been translated into clinical settings to of life and cause significant disability even develop and validate new disease-screening for conditions that are not immediately life- protocols, effective prevention strategies, threatening. Debilitating symptoms—such as including vaccines, and innovative behavioral, chronic pain, discomfort, , diarrhea, pharmacological, and surgical treatments. constipation, incontinence, social stigma, or embarrassment—that are associated with The incidence of acute hepatitis B has many GI disorders can impact patients’ ability plummeted in the U.S. due in part to the to work or engage in everyday activities. introduction of a vaccine to the virus that Collectively, these diseases account for over causes this disease. The development of tests $44 billion in indirect costs associated with that detect the presence of hepatitis B and disability and mortality each year. C viruses in blood has nearly eliminated their transmission through blood donation, Although digestive diseases in general can further reducing the public health threat of affect individuals of any age, race or ethnicity, viral hepatitis. Likewise, the annual number gender, or socioeconomic status, some diseases of deaths from colorectal cancer has been disproportionately affect certain populations. For declining in recent years. This decrease may be example, necrotizing enterocolitis occurs only partially attributable to the availability of cost- in newborns, while diverticular disease is most effective screening techniques that improve the frequently diagnosed in the elderly. The rate of likelihood of detecting the disease at an early some infectious GI diseases such as H. pylori and stage when it is more responsive to treatment. hepatitis B—both of which increase the risk of Research on inflammatory bowel diseases digestive cancers—is substantially higher among (IBD) supported the development of biologically certain groups that emigrate from areas where based therapies, including multiple monoclonal these diseases are endemic, such as parts of Asia. antibodies directed against tumor necrosis Autoimmune diseases like celiac disease and factor (TNF), that have provided relief for many inflammatory bowel diseases are more common IBD patients who did not respond to other in women. African Americans have a higher treatments. Finally, the discovery that ulcers incidence of pancreatic cancer than any other can be caused by H. pylori infection quickly led racial/ethnic group in the U.S. and have a poorer to the realization that many ulcer patients can prognosis at diagnosis. These and other significant be cured by antibiotics. health disparities provide both opportunities and challenges for research to reduce the public health These and other advances have truly burden of digestive diseases. revolutionized the care of many digestive disease patients or those who are at risk for developing digestive diseases. However, the NIH-supported digestive diseases burden of digestive diseases in the U.S. remains research significant, and the sheer number and variety of these illnesses highlight the crucial need for Advances and Opportunities ongoing attention to these diseases through a vigorous research effort. For example, very Decades of research in digestive diseases have little is known about the causes of functional significantly contributed to a reduction in the GI disorders, and individuals affected by burden of many of these diseases on individual these conditions have few treatment options.

 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Likewise, patients with chronic pancreatitis Table 1: NIH Expenditures for Digestive often experience severe pain that is difficult Diseases Research FY 2007 (in dollars) to treat and can substantially reduce quality of life. Cancer of the digestive system remains NIH Institute, Center, FY 2007 an important cause of cancer-related death in Office or Fund* the U.S. For these patients and the millions of other Americans afflicted with acute or chronic NCI 395,479,000 digestive diseases, the National Commission NIDDK 331,021,000 on Digestive Diseases sought to identify the NIAID 273,792,000 most critical needs and promising opportunities NIDCR 83,650,000 in digestive diseases research that have NIEHS 32,865,000 the potential, if pursued, to advance the NCRR 26,481,000 understanding of all forms of digestive diseases NIAAA 24,124,000 and alleviate the burden of these diseases. NHLBI 15,477,000 NICHD 14,705,000 Digestive Diseases Research Funding NINDS 9,446,000 Progress in digestive diseases research has NCCAM 9,253,000 benefited from strong support from theNational ROADMAP 8,014,000 Institutes of Health (NIH) in recent years. NINR 2,638,000 Twenty NIH Institutes, Centers, and Offices NIA 1,900,000 currently support digestive diseases research FIC 1,234,000 on a variety of topics with a total expenditure of NIDA 1,055,000 more than $1.2 billion in fiscal year 2007 OD 910,000 (Table 1). NIBIB 794,000 NIMH 550,000 The NIH research portfolio includes funding for studies of fundamental mechanisms of NHGRI 506,000 digestive system development and function, NCMHD 194,000 as well as basic, translational, and clinical TOTAL NIH 1,234,088,000 research on the digestive system in normal *See text for full titles of acronyms. states and disease conditions. NIH research is funded through grants, awards, contracts, and fellowships to extramural researchers and institutions for research and training, as well as support for intramural laboratories. To aid in the development of this long-range research plan, lists of grants and other awards comprising the NIH portfolio for digestive diseases were provided to members of the Commission and to each working group.1

1 Table 1 provides the most recent NIH funding data (FY 2007) as of the completion of this research plan in spring 2008. The Commission’s charter required a scientific overview of NIH-funded research and research-related activities. In response to that mandate, the Commission and its working groups were provided with the most recently available, aggregate funding data and lists of digestive diseases-related NIH research awards during the course of their discussions and development of research goals, which took place in 2006-2007. The FY 2006 award list used by the Commission will be made available on the Commission’s website at http://NCDD.niddk.nih.gov.

Introduction 15 Institutes and Centers accounting for the Other NIH Institutes, Centers, and Offices that majority of the NIH portfolio for digestive support digestive diseases research and research diseases research and research training training include: (Figure 1) include: ß National , , and Blood Institute ß National Cancer Institute (NCI, 32 percent) (NHLBI) ß National Institute of Diabetes and Digestive ß Eunice Kennedy Shriver National Institute and Kidney Diseases (NIDDK, 27 percent) of Child Health and Human Development ß National Institute of and Infectious (NICHD) Diseases (NIAID, 22 percent) ß National Institute of Neurological Disorders ß National Institute of Dental and and Stroke (NINDS) Craniofacial Research (NIDCR, 7 percent) ß National Center for Complementary and ß National Institute of Environmental Health (NCCAM) Sciences (NIEHS, 3 percent) ß NIH Roadmap for Medical Research ß National Center for Research Resources (ROADMAP) (NCRR, 2 percent) ß National Institute of Research (NINR) ß National Institute on Alcohol Abuse and ß National Institute on Aging (NIA) Alcoholism (NIAAA, 2 percent) ß Fogarty International Center (FIC) ß National Institute on Drug Abuse (NIDA) ß NIH Office of the Director OD)( Figure 1: NIH Awards for Digestive ß National Institute of Biomedical Imaging and Diseases Research by Institute or Center Bioengineering (NIBIB) (FY 2007) ß National Institute of Mental Health (NIMH) ß National Human Genome Research Institute (NHGRI) NIAAA Other 2% NCRR 5% ß National Center on Minority Health and 2% Health Disparities (NCMHD) NIEHS 3% NCI 32% Coordination and Communication of Digestive Diseases Research NIDCR 7% In addition to its direct role in funding digestive diseases research, the NIH engages in significant efforts to coordinate research programs within the agency and with other NIAID 22% Federal agencies that share a common interest in combating digestive diseases. The Digestive Diseases Interagency Coordinating Committee NIDDK (DDICC) is the primary mechanism for Federal 27% digestive diseases research coordination. The DDICC brings together representatives from multiple NIH Institutes and Centers that fund digestive diseases research, as well as from other agencies, including the Agency for Healthcare Research and Quality, the Food and Drug Administration, the Department of Defense, the

16 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Centers for Disease Control and Prevention, professionals, and the general public. This the Department of Veterans Affairs, the Health service includes distribution of public Resources and Services Administration, and information materials on a variety of digestive the Department of Agriculture, to discuss and diseases, referrals to health professionals, coordinate digestive diseases-related research and a reference collection on health education activities across the Federal Government. The publications. Liver Disease Subcommittee of the DDICC coordinates liver and biliary diseases research across the NIH and other Federal agencies, Genesis Of The National including efforts to implement the trans-NIH Commission On Digestive Diseases Action Plan for Liver Disease Research. And Its Long-range Research Plan For Digestive Diseases The NIH also promotes communication and collaboration within the digestive diseases Charter for the National Commission on research community through the support of Digestive Diseases conferences and workshops. For example, the NIH convened a state-of-the-science conference Elias A. Zerhouni, M.D., Director of the National on prevention of fecal and urinary incontinence Institutes of Health, chartered the National in adults to assess the scientific evidence Commission on Digestive Diseases on July 26, relevant to understanding the epidemiology, risk 2005, based on a mutual interest in advancing factors, burden of illness, prevention strategies, digestive diseases research shared by the NIH and research priorities for these serious medical and the Congress. The establishment of the conditions. Other conferences have focused on Commission responds, in part, to congressional diverse topics relevant to digestive diseases report language accompanying the FY 2005 including: gastrointestinal microbiota and appropriations bills in the House and Senate for pre/probiotics research; nuclear receptors in the Departments of Labor, Health and Human liver and digestive disease; improving long-term Services, and Education, and Related Agencies. outcomes for pediatric liver transplantation; The Commission was charged with two main acute ; alcohol, intestinal bacterial tasks: (1) to conduct an overview of the state growth, intestinal permeability to endotoxin, of the science in digestive diseases research and medical consequences; screening and exclusive of diseases of the oral cavity, and (2) outcomes in ; and management to develop a 10-year plan for digestive diseases of hepatitis B. Many of these conferences and research that is consistent with the NIH mission workshops are jointly sponsored by multiple and aimed at the ultimate goal of improving NIH Institutes and Centers, other Federal the health of the Nation through research. agencies, and private, professional, or patient The Commission’s primary focus has been to advocacy organizations. identify compelling research opportunities that, if pursued, would improve the lives and health of The National Digestive Diseases Information individuals affected by digestive diseases. Clearinghouse2 was established by NIDDK in 1980 to increase knowledge and understanding The long-range research plan developed by about digestive diseases among people with the Commission, entitled Opportunities and these conditions and their families, healthcare Challenges in Digestive Diseases Research:

2 The National Digestive Diseases Information Clearinghouse is accessible online at: http://digestive.niddk.nih.gov/.

Introduction 17 Recommendations of the National Commission diseases research, served on the Commission on Digestive Diseases, will serve as an important (Appendix 2). The Commission was chaired by guide to help defineNIH priorities for digestive Stephen P. James, M.D., Director of the Division diseases research over the next decade. Thus, the of Digestive Diseases and Nutrition of the plan encompasses many broad areas of digestive NIDDK, which is the lead entity for coordination diseases research that are relevant to the NIH of digestive diseases research at NIH. mission, including fundamental biology of the digestive system and disease-oriented research Shortly after the Commission’s establishment, topics such as: epidemiology; environmental the members created “working groups” of factors; genetics; mechanisms; diagnosis; causes; additional external experts to provide input to treatments; behavioral, social, and psychological the Commission for developing the individual factors; health disparities; prevention; and cures. chapters of the research plan. Therefore, Opportunities identified by theCommission a second public nomination process was span basic, translational, and clinical research, undertaken to solicit suggestions for members including clinical trials in children, adults, and of each working group. Approximately six to in special populations such as high-risk groups ten members were chosen for each group based or the disadvantaged. The plan also addresses on their expertise and knowledge of current issues related to research training and education research related to the working group topic. of investigators in digestive diseases research Members included individuals from recently fields. Finally, this research plan identifies convened groups, such as the Liver Disease challenges to its optimal implementation and Subcommittee of the DDICC and NCI’s GI- proposes cross-cutting, innovative disciplines, related Progress Review Groups, in order to technologies, and resources that would create complement and build upon those efforts. Due research synergies and promote progress in to the scientific nature of the working group digestive diseases research. reports, members were primarily researchers and healthcare providers with expertise in Development and Organization of the digestive diseases research (Appendix 2). Commission Working group members served in an advisory role to the Commission, and each working group Appointment of Commission Members and was led by a Chair and Vice Chair selected from Formation of Working Groups among the members of the Commission.

The NIH Director appointed 16 Commission A Collaborative and Inclusive Research members who included extramural researchers Planning Process from academic institutions across the country, medical professionals, and patient advocates Once the full Commission was seated, it met (Appendix 2). These members were selected five times and communicated extensively from more than 100 names submitted through a via conference calls and emails to conduct nomination process that was open to the entire business in pursuit of its mission. All meetings research community and the general public. In were open to the public and advertised in addition, 22 ex officio members representing advance by notification through the Federal NIH Institutes and Centers, as well as other Register and through the Commission’s public Federal agencies with an interest in digestive website,3 as well as by updates sent to all major

3 The website of the National Commission on Digestive Diseases can be accessed at: http://NCDD.niddk.nih.gov.

18 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases digestive disease organizations. Summaries of June 18-19, 2007 (Arlington, VA) – This meeting proceedings were also posted on the meeting focused on identifying the highest- Commission website for the information of the priority research goals, objectives, and public. Commission meetings included: challenges, as well as major cross-cutting themes, for inclusion in the long-range research June 12, 2006 (Arlington, VA) – At its first plan. It was necessary for the Commission to meeting, the Commission received its charge carefully review the many excellent research from Griffin Rodgers, M.D., then Acting goals proposed by the working groups and Director of the NIDDK, on behalf of the NIH determine which would potentially have the Director, Dr. Zerhouni. The Commission most impact on digestive diseases if pursued members also discussed plans by the NIH to by the NIH. Thus, the Commission focused update epidemiologic data on the burden of on developing a set of recommendations for digestive diseases in the U.S. Representatives high-priority goals that would be wide-ranging, from NIH Institutes and Centers and other yet manageable, in scope. Based on discussions Federal agencies provided an overview of at this meeting, working group chairs were digestive diseases research activities being charged with drafting a chapter for inclusion carried out within each organization. With in the long-range research plan. Elizabeth this background in mind, the Commission Wilder, Ph.D., Acting Associate Director of deliberated on the overall structure of the final the Office of Portfolio Analysis and Strategic long-range research plan and defined general Initiatives (OPASI) in the NIH Office of issues to be addressed in each chapter. The the Director, updated the Commission on list of chapters for the research plan and the progress and planning for the NIH Roadmap appointment of chairs for the corresponding for Medical Research, which provides virtual working groups were finalized by ongoing “incubator space” for NIH programs of cross- communication after the meeting. disciplinary relevance or complexity. The Human Microbiome Project, launched in 2007, November 6, 2006 (Arlington, VA) – The is an example of a Roadmap program that primary purpose of this meeting was to review is of key importance to advancing digestive progress reports from each working group. diseases research. Following the meeting, the The chairs of each group described: the major presentation materials were posted on the points of the background/introduction for each Commission’s public website. topic-specific chapter; the scientific scope of the chapter; areas of potential overlap with November 19, 2007 (Rosemont, IL) – At this other chapters; and progress made on naming meeting, Dr. Griffin Rodgers, Director ofNIDDK, the working group members and developing commended the Commission on its work to date material for the research plan. Commission and encouraged continued public involvement members identified potential gaps in the in the development and implementation of proposed outline for each chapter and resolved the research plan for digestive diseases. The overlap issues among chapters with related Commission was also provided an update of interests. In addition, Dr. Zerhouni addressed progress on the development of a report on the Commission on the importance of its the burden of digestive diseases in the U.S. task in relation to the broader NIH vision for Most importantly, the Commission reviewed biomedical research and public health, as well and discussed a draft of the entire long-range as the current challenges being faced by NIH research plan for the purpose of re-organizing research programs. potential overlapping or duplicative research goals and filling in gaps in the research plan.

Introduction 19 Based on discussions at this meeting, the expertise. Finally, each working group had an members made final changes to their assigned opportunity to review and comment on a draft of draft chapters and prepared the research plan the chapter for their assigned topic. for a public comment period. In the interim, the presentation materials from this meeting were Public Comments posted on the Commission’s public website. A draft of the long-range research plan was May 16, 2008 (San Diego, CA) – At its fifth posted on the Commission’s website in spring and final meeting, theCommission reviewed 2008 for a 30-day public comment period. the near-final draft research plan that Comments and suggestions received from incorporated suggestions submitted during members of the research community, patient the public comment period. The Commission advocacy and professional organizations, discussed the feasibility of prioritizing its and the public at large were reviewed by the recommendations without detracting from Commission and incorporated into the final the inclusive nature of the research plan, research plan as appropriate before transmittal which addresses multiple digestive diseases. to the NIH Director and the Congress. Mechanisms or organizational structures for overseeing the implementation of the Organization of the Long-Range recommendations for research set forth in the Research Plan plan were also considered. The Commission received an update on data developed for the This long-range research plan for digestive report on the burden of digestive diseases in diseases is intended to be comprehensive, the U.S. Finally, Dr. Rodgers presented each yet manageable, in size and scope. While appointed member of the Commission with acknowledging the vast number of digestive a certificate signed by Dr. Zerhouni and Dr. diseases and conditions that affect human James in recognition of their efforts over the health, the Commission chose an organizational previous 2 years. In response to discussions at structure for the research plan that categorizes this meeting, final additions and revisions were diseases by common etiology, mechanism, made to the recommendations for the research affected , or other considerations. goals, and the Commission voted to approve the Although there are numerous common and rare research plan in August 2008. digestive diseases that have a serious impact on the daily lives and health of people throughout Working Group Meetings the Nation, it was not possible to mention every digestive disease by name in this research plan. In addition to the public meetings of the Rather, the Commission noted that many of the Commission, each working group engaged recommendations are expected to have a broad in one or two conference calls to discuss and impact on diseases of the digestive system, prioritize research advances, goals for future including those not explicitly mentioned. The research, and major challenges and steps that Commission also acknowledged that many would be needed to achieve the research goals. research topics or disease areas would be relevant Working group members consulted informally to more than one theme within the research with additional experts and colleagues from the plan. To limit redundancy, topics were assigned scientific, medical, and patient communities to to a single chapter as much as possible, with ensure that the final long-range research plan some cross-referencing where appropriate. For draws upon a broad range of perspectives and example, colorectal cancer research is addressed

20 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases primarily in the disease-oriented chapter on ß Inflammatory Bowel Diseases: Diseases Cancers of the Digestive System rather than in associated with chronic inflammation of the organ-based chapter on Diseases of the Colon the GI tract, including ulcerative and and Rectum. Therefore, readers are encouraged to Crohn’s disease. view this research plan in its entirety in order to locate all relevant text on a given topic. ß Intestinal Failure and Regeneration, Nutritional Disorders and Support,4 Topic-specific areas chosen for organizing Surgically Modified Gut,5 and Transplantation: content with the long-range research plan are: Conditions arising from challenges to the physical integrity of the GI tract, including ß Research on the Basic Biology of the Digestive short bowel syndrome, intestinal failure, System: Basic developmental biology and intestinal transplantation, and surgically function of the digestive system, including modified gut, as well asnutritional support growth and integrative , digestion strategies for patients with these conditions. and metabolism, nutrient and fluidabsorption and secretion, neurophysiology and motility, ß Diseases of the Oropharynx and Esophagus: and satiety, microbiology and Disorders affecting the oropharynx and microbial-host interactions, and mucosal esophagus, including swallowing disorders immunology. (), GERD, Barrett’s esophagus, achalasia, eosinophilic esophagitis, and others. ß Functional Gastrointestinal Disorders and Motility Disorders: Functional diseases ß Diseases of the Stomach and Small Intestine: for which no anatomic abnormality can Disorders affecting the stomach and small be discerned and diseases associated with intestine, including peptic ulcer disease, neuromuscular dysfunction, including diarrheal diseases, celiac disease, necrotizing irritable bowel syndrome, functional enterocolitis, eosinophilic GI disease, dyspepsia, gastroesophageal reflux disease and others. (GERD), gastroparesis, chronic intestinal pseudoobstruction, and others. ß Diseases of the Colon and Rectum: Disorders affecting the colon and rectum, ß Infections of the Gastrointestinal Tract: including diverticular disease, fistulas,fecal Diseases caused by virulent bacteria, viruses, incontinence, colonic ischemia, angioectasias, or other parasites that infect the digestive appendicitis, , and others. system, such as E. coli-associated diseases, cholera, C. difficile infection, and others. ß Diseases of the Pancreas: Disorders affecting the pancreas, including acute and chronic ß Cancers of the Digestive System: Cancers of pancreatitis, cystic lesions of the pancreas, and the esophagus, stomach, pancreas, colon and cystic fibrosis. rectum, and rare GI cancers.

4 The topic of nutrition was not explicitly included in the Commission’s charter because research planning in this area is overseen by the existing NIH Nutrition Coordinating Committee within the Division of Nutrition Research Coordination, NIH. Nonetheless, nutritional issues and nutrition science are critically important to many digestive diseases topic areas and are addressed in the research plan as appropriate.

5 Obesity, which is a major public health threat in the U.S., was not specifically chosen as an overarching topic for theCommission’s research plan because it is addressed by the existing NIH Obesity Research Task Force, which released its Strategic Plan for NIH Obesity Research in August 2004. However, the relationship of obesity and digestive diseases is incorporated into the research plan as appropriate, for example with respect to challenges and opportunities in bariatric .

Introduction 21 ß Diseases of the Liver and Biliary System: 6 that could benefit patients are highlighted. Disorders affecting the liver and biliary system, These advances do not represent a including viral hepatitis, , comprehensive survey of all progress in drug-induced liver disease, autoimmune liver digestive diseases research, but are meant diseases, liver transplantation, , to indicate major, paradigm-shifting gallstones, and others. discoveries that point to new opportunities for further investigation. ß Bioengineering, Biotechnology, and Imaging: Development of innovative techniques and ß Goals for Research: High-impact, state-of-the-art technologies for detection, forward-looking, research-oriented goals diagnosis, and treatment of digestive are described that capitalize on new diseases, including endoscopic techniques, opportunities and challenges in digestive imaging modalities, minimally invasive diseases research. Collectively, the research surgical procedures, tissue engineering goals in each chapter represent those and , and simulation identified by theCommission as the highest- training. priority aims to be achieved in digestive diseases research over the next 10 years. The Each topic-specific chapter in the long-range goals are numbered solely for ease of future research plan addresses one of the major reference and are not listed in priority order. topic areas identified by the Commission and Each goal includes a short list of specific is organized along a common format with objectives that represent more discrete, the following sections (except the chapter on shorter term steps toward achieving the Diseases of the Liver and Biliary System, which overall goal. presents this information in a slightly different format due to its relationship to the trans-NIH ß Major Challenges and Steps To Achieve Action Plan for Liver Disease Research): the Research Goals: Barriers to conducting research and to achieving the group of goals ß Summary of Research Goals: Major, high- for each topic area are described. In addition, priority research goals are summarized at this section identifies important steps that, the beginning of each chapter. if taken, would help overcome these barriers and accelerate progress toward realizing the ß Introduction and Background: An overview research goals. of the topic, common conditions and their disease burden, epidemiology, current Finally, the Commission’s research plan understanding of pathogenesis and natural concludes with a summary of common history, and current means of control, cure, themes and steps for implementation that and/or prevention are provided. were identified by multiple working groups as important research goals and challenges. ß Recent Research Advances: Research These common themes are broadly applicable findings that have had a significant impact to many digestive diseases or questions on digestive diseases research, patient in basic biology of the digestive system. In health, or the ability to do future research particular, the Commission recognized the

6 A major strategic planning effort in the area of liver and biliary system diseases was accomplished with the release of the trans-NIH Action Plan for Liver Disease Research in December 2004. The Commission working group assigned to this area was charged with identifying research opportunities that build on, rather than duplicate, recommendations from the Action Plan. The Action Plan is accessible online at: http://liverplan.niddk.nih.gov/.

22 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases fundamental importance of finding ways The steps proposed to aid in implementation of to achieve and sustain a robust pipeline of the research address current gaps in scientific trained investigators with knowledge of knowledge and critical opportunities for NIH and a commitment to digestive diseases research and training efforts over the next research. Many topic-specific chapters decade that have the potential to impact identify specialized areas of research training multiple areas of digestive diseases research. or recruitment that would help to sustain Pursuing these opportunities will allow the NIH the investigator pool in specific fields of and the research community to find innovative research. In addition, a working group of solutions to reduce the toll that digestive Commission members developed goals and diseases take on the health and quality of life of recommendations for research training, individuals throughout this Nation. education, and the recruitment of new investigators to digestive diseases research; these recommendations are described in the Conclusion: Common Themes and Steps for Implementation chapter.

Introduction 23 Photomicrograph showing expression of the Lgr5-lacZ reporter gene in the base of small intestinal crypts in adult mice. Through this type of research, scientists have been able to identify stem cells within the adult intestine that are capable of forming the cell types needed to continually renew this organ throughout life.

Image courtesy of Dr. Hans Clevers. Reprinted by permission from MacMillan Publishers Ltd: Nature, 449:1003-1007, copyright 2007.

 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Research on the Basic Biology of the Digestive System

SUMMARY OF RESEARCH GOALS

The Commission proposes multiple research goals to achieve the overarching mission of understanding the basic biologic underpinnings of the structurally and functionally complex digestive system.

Developing new technologies to isolate, characterize, cultivate, and manipulate stem cells of the digestive system may provide new approaches to understand the pathogenesis and develop new therapies for digestive diseases. Uncovering the mechanisms that control development and differentiation of the digestive tract before birth and in neonatal life could generate new insights for regenerative therapies to treat digestive cancers and other diseases, as well as provide new insights into disease pathogenesis.

Studying the fundamental mechanisms of digestion could point to new strategies for treating disorders of nutrient and fluidabsorption, secretion, and metabolism. The enteric nervous system links the digestive system and the brain and controls motility within the gastrointestinal (GI) tract. Research on the function and organization of the enteric nervous system will enable a better understanding of gut motility in digestive health and disease. The intestinal microflora are essential to normal digestive function; studying the composition and activity of commensal organisms in healthy individuals could reveal important links between alterations in the microflora and human disease. Finally, themucosal immune system is a critical component of the body’s defenses against disease. Understanding the mechanisms by which this system operates could lead to new vaccination strategies or other approaches to prevent or treat infectious diseases that affect the digestive system.

Research on the Basic Biology of the Digestive System 25 INTRODUCTION AND BACKGROUND bowel cancers are all related to development of the embryonic gut. GI development has long Understanding the basic biologic functions of been a priority for the NIH, which supported the digestive system, which includes the GI visionary research leading to improved tract, pancreas, biliary system, and liver, is understanding of specification, of fundamental importance to the diagnosis patterning, stem cell kinetics, and crypt-villus and treatment of all diseases related to organization. This field is now in a position to these organ systems. This research plan dissect the molecular basis of GI development, of the National Commission on Digestive which holds enormous promise for Diseases therefore begins with an overview of understanding pathophysiology and therapy. several areas of biology that have broad and overarching relevance for diseases covered Growth and integrative physiology: The in subsequent chapters of this research digestive system is a complex collection of plan. These overarching biologic pathways organs that facilitates the intake, processing, include those related to the following topics and absorption of food and water while that have seen enormous growth in scientific maintaining an effective barrier from the knowledge, poising them to lead to future external environment. It is highly flexible and therapies. They include: development (e.g., responds to varying nutritional and disease cancer and normal/abnormal development states by altering its structure and function. of cells and tissues of all organ systems); Understanding the mechanisms that lead growth and integrative physiology (e.g., multi- to gut growth and remodeling in health and organ diseases); digestion and metabolism disease is, therefore, critical for development (e.g., intestinal failure, disorders, and of therapeutics to treat a wide variety of pancreatic insufficiency); nutrient and fluid digestive problems, including intestinal failure absorption and secretion (e.g., diarrhea and and obesity. Maintenance of digestive health ); neurophysiology and motility requires integration of gut physiology with (e.g., irritable bowel syndrome [IBS], obesity, the functions of other tissues and systems, and metabolic syndrome); microbiology and including , the brain and peripheral the microbiome (e.g., infectious diseases); and nervous systems, and the immune system. mucosal immunology (e.g., inflammatory bowel diseases [IBD] and vaccines against enteric Digestion and metabolism: In the last ). To accomplish the goals of this several years, increased understanding of chapter, three themes of common importance many pathways involved in intestinal nutrient to these areas of investigation need to be absorption has resulted from our expanding addressed: the identification, characterization knowledge of the hierarchy of membrane and manipulation of intestinal epithelial stem transporters with distinct substrate specificity, cells; development of techniques to characterize as well as a refined understanding of their and manipulate the human intestinal subcellular itineraries and regulation. microflora; and delineation of and methods to Researchers have identified intracellular target inflammatory pathways of the intestines, acceptor molecules and nuclear stomach, pancreas, and hepatobiliary system. receptors that participate in metabolic channeling, as well as nutrient sensing, Development: Congenital malformations, and that signal through both import and IBD, certain malabsorption syndromes, export pumps. Finally, the signaling dialogue epithelial metaplasia, disorders of motility, and between the host and the microbiome has been

26 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases explored. Together, these advances have yielded adult gut and undergo changes in self-renewal enormous implications for understanding and suggests that replacement therapy can enhancing the relationship between nutrition become a reality. and digestive health. Microbiology and microbial-host Nutrient and fluidabsorption and interactions: The microbial population secretion: Using both functional and genetic that normally inhabits the human GI tract, approaches, many membrane transport proteins especially the colon, is one of the densest mediating intestinal salt, solute, and water microbial populations known (approximately transport have been defined over the past 10 1012 per gram of intestinal contents), years. While there will be a continuing need to accounting for at least 30 percent of the identify the proteins mediating and regulating volume of colon contents. This highly complex absorption and secretion, the real challenge of population, containing thousands of bacterial the next decade is to leverage this information species, is acquired shortly after birth and about the building blocks of fluid and nutrient persists in the colon throughout life. The movement into an integrated view of epithelial colonic microflora have a major impact on function. Given the centrality of the epithelial human health that includes a role in human cell to a wide range of digestive diseases and nutrition, stimulation of mucosal cell turnover, responses to disease, such information has broad suppression of intestinal pathogens such and enabling implications. as Clostridium difficile, and as a reservoir for resistance genes. Members of Neurophysiology and motility: In recent the microflora are also significant causes years, much knowledge has been gained about of post-surgical infections and infections in neural-hormonal control of gut functions cancer patients. Less clearly established are a and energy homeostasis. Unraveling the number of suspected, but still unproven, links complexity of signaling between diverse to such conditions as IBD, colon cancer, and cells in the enteric nervous system (ENS) obesity. Despite its importance, little is known provides the cellular and molecular basis about either the composition or functions of for understanding many disorders in which this vast microbial community within the the ENS plays a role. Characterization of human intestine. the neurobiology of brain-gut interactions provides the necessary conceptual framework Mucosal immunology: The mucosal immune for developing new treatments of functional system encompasses a constellation of GI diseases and motility disorders. Under- specialized cells and structures that enable the standing the mechanisms governing nutrient function of the immune system at the site of its sensing and secretion by enteroendo- greatest exposure to the microbial environment: crine cells allows investigators to exploit these the mucosal tissues of the intestines and their pathways in the development of new agents affiliated structures. Understanding the many to combat obesity and diabetes. A better unique functions of this system will lead to a understanding of the molecular mechanisms better understanding of mucosal infections, leading to disease and age-related apoptotic including HIV infection, may permit the cell death provides hope for preventive and/or development of mucosal vaccines, and may lead regenerative therapy. Finally, the revelation to better treatments for immunologic diseases of that stem cells persist in the the mucosa, such as IBD and celiac disease.

Research on the Basic Biology of the Digestive System 27 RECENT RESEARCH ADVANCES precursors of some embryonic digestive organs. In parallel, cancer biologists are gaining a Digestive System Development better understanding of epithelial-stromal (mesenchymal) interactions in neoplasia; thus, Development of the crypt-villus axis the principles of developmental interactions in digestive organs are likely to extend into the The critical roles of the Wnt, Notch, Hedgehog, realm of tumor biology. BMP, Lgr5, and FGF signaling pathways have been elucidated in intestinal crypt homeostasis Growth and Integrative Physiology and in distinguishing the functions of crypt progenitors and the intestinal epithelial stem Molecular events underlying intestinal cell from those of differentiated villus epithelial growth and adaptation cells. These advances provide important insights into the genetic basis of colorectal Significant progress has been made in cancer—the second leading cause of U.S. cancer understanding changes in gene expression deaths—and to epithelial stem cell homeostatic and cell signaling pathways that are induced mechanisms, as well as to normal development by the loss of intestinal mass, such as occurs and inflammation. It is increasingly clear that during and other gut injuries Wnt signaling maintains proliferative capacity and during the adaptive response that follows and lack of differentiation in crypts; its absence injury. Maintenance of intestinal homeostasis permits differentiation in villi; and constitutive during development and adult life requires Wnt activity is responsible in large part for a proper balance among cell proliferation, dysregulated cell proliferation in colorectal and , and differentiation and involves other GI tumors. interactions between epithelial and other cell types in the intestinal wall, including Mechanisms that pattern the mesenchymal cells, such as fibroblasts. undifferentiated embryonic gut tube Understanding the molecular pathways that into individual digestive organs mediate normal intestinal growth and the response to injury and how extrinsic stimuli, The GI tract and its evaginated derivatives such as nutrients, affect their activity is (liver, pancreas, and biliary system) are a crucial for development of interventions to paradigm for inductive tissue interactions in maintain intestinal mass and function. In development and, in particular, epithelial- particular, studies to elucidate the stem cell mesenchymal interactions in organogenesis. niche response following gut resection or injury Recent studies help define how undifferentiated (e.g., from ischemia, radiation, or trauma) may endoderm is specified during embryogenesis provide novel therapeutic targets to enhance in response to extraneous signals and the gut mass and function. activities of tissue-restricted transcription factors and indicate how these activities Regulation of intestinal growth: roles combine to confer tissue- and organ-specific of nutrients, trophic factors, and properties. The identity of some tissue- neurohumoral signaling restricted transcription factors that regulate gut development is known, though many Evidence from animal models and human others remain to be discovered. There is also subjects with short bowel syndrome suggests growing, though still limited, understanding that intestinal adaptive growth is regulated of chromatin states that distinguish the by several key hormonal mediators, including

28 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases -like peptide-2 (GLP-2), -like pathways may underlie the altered motility, -1 (IGF-1), epidermal growth secretion, and sensation seen in inflammatory factor, and . However, their gut disorders. mechanisms are still poorly understood, including the involvement of other cell types Digestion and Metabolism besides in the intestinal growth- stimulating effects. Diversity in genetic pathways for absorption of and other sterols Integration of brain-gut signaling, metabolism, and mucosal biology in the An membrane transporter (NPC1L1) regulation of body mass specific for intestinalcholesterol uptake has been identified. Research has also advanced the Considerable progress has been made in understanding of the sensing and discrimination understanding how the presence of nutrient of subtle structural differences between stimuli in the gut lumen is sensed by endocrine cholesterol and plant sterols (sitosterol) and cells and nerves. This information is crucial identification of sterol efflux pumps (ABCG5/G8) in the normal digestive processes that occur that minimize entry of plant-derived cholesterol in the gut and may be altered in disease. The mimics into the systemic circulation through presence of luminal nutrients is also important selective export into the lumen. The basolateral in the short-term regulation of food intake. cholesterol efflux-pump, ABCA1, has been Evidence from rodent models and human identified, and its importance in the production studies suggests that two GI hormones, CCK of plasma HDL has been defined. Collectively, and PYY, are involved in the regulation of food these advances have greatly expanded our intake via activation of neural substrates in the understanding of the complexities of whole body brain-gut axis. Moreover, long-term changes in cholesterol homeostasis in health and disease. the macronutrient content of the diet can alter the sensitivity of the brain-gut axis and may Hierarchy of ligands and receptors for lead to changes in body mass. intracellular signaling or metabolic compartmentalization of nutrients Role of the nervous system in GI inflammation The role of nuclear hormone receptors (FXR, LXR, PPARs) and other transporter/acceptor Research has provided new insights into proteins (FABPs/FATPs) in energy sensing neuroimmune relationships that may and in the maintenance of weight has been facilitate translation of basic science into uncovered. In addition, new information therapeutic applications, particularly with concerning the metabolic compartmentalization regard to GI inflammatory diseases. One of fatty acids (DGAT1/DGAT2) and mono- example is the cholinergic anti-inflammatory glycerides (MGAT1/MGAT2) has provided pathway, which modulates release of pro- novel targets for obesity treatment. Finally, the inflammatory mediators in models ofcolitis, development of innovative systems to probe the ischemia-reperfusion, postoperative , and dialogue between the host and luminal bacteria pancreatitis. Neuronal signaling pathways in has expanded understanding of the relevance of the gut are affected by inflammation; studies the luminal bacterial environment to digestive suggest that changes in function of the mucosal and absorptive functions. serotonin transporter and other neural

Research on the Basic Biology of the Digestive System 29 Novel functions for genes involved in Epithelial barrier function intestinal lipid absorption Researchers are investigating the molecular Conserved pathways in intestinal and hepatic basis for the regulation of barrier function. lipid absorption have been implicated in lipid Elucidation of the function of claudins, presentation and innate immunity. In occludin, and other tight junction proteins is particular, emerging data strongly suggest that progressing rapidly. The coordinated action the microsomal transfer of TNF-α on barrier function and absorptive is responsible not only for lipidation of the transporters, without effect on chloride export protein apoB, but also for lipid antigen secretion, is a new and important facet of presentation by the major histocompatibility intestinal regulation. Specialized mechanisms molecule CD1d. In addition, research by which intestinal epithelial cells actively indicates that apolipoproteins involved in contribute to body defense through secretion lipid export (apoE) also participate in lipid of antibacterial and repair of a antigen presentation by CD1 molecules. Also disrupted epithelial layer are being defined. noteworthy is the discovery that the peptide Complementary to understanding the barrier transporter, hPEPT1, may play a role in is research on the molecular basis of cellular bacterial peptide presentation. water transport. Cloning of water channel (aquaporin) molecules in 1991 opened the Nutrient and Fluid Absorption door for advances in understanding cell and and Secretion tissue fluid transport and led to the awarding of the 2003 Nobel Prize in Chemistry. Blurring of classical boundaries of Research on water channels sets the stage for absorptive and secretory cell types understanding the pathways regulating barrier function versus fluid transport function. The intestinal is composed of a variety of cell types that are intermingled in a Gut factors and epigenetic regulation of single layer that serves as a primary barrier food intake and energy metabolism separating the gut lumen from the body. Studies of intestinal epithelial development The discovery of non-mutational regulation of have revealed new pathways that regulate the gene expression that can be passed through balance among these different cell types, most generations has ushered in an era of new notably Wnt signaling in regulating epithelial understanding about disease predisposition. proliferation, as well as Math-1 and Gfi in For example, studies have shown that the regulating the census of secretory cell types. offspring of European women undergoing The molecular pathway for intestinal epithelial starvation during World War II are predisposed differentiation to absorptive cell types has to a higher incidence of diabetes. These yet to be established. With the constellation observations validate a need for more studies to of absorptive and secretory proteins being evaluate this mode of regulation. The study of defined, there is also increased interest in nutrient absorption is now integrating data on distinguishing gradations of function. Recent the regulation of food intake (satiety). studies have revealed fluid and is a recently discovered that absorptive functions in the structures of the displays strong growth hormone-releasing colonic crypt that challenge our understanding activity and has a stimulatory effect on food of how the works in intake and digestive function while reducing health and disease. energy expenditure. Research on ghrelin has

30 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases led to new insights into how this hormone in patients with a variety of motility disorders. produced by the stomach connects the Glial cells play an important role in synaptic endocrine control of nutritional homeostasis transmission plasticity and immune protection. through the brain-gut interactions. The neurotrophic factors that are produced by glial cells have strong anti-apoptotic Characterization of absorption effects on colonic epithelial cells, which may be responsible for their protective actions It is widely recognized that iron homeostasis during mucosal inflammation. Understanding in the body is almost exclusively regulated at the cellular elements within the ENS will be the level of intestinal iron absorption because, critical to understanding its physiology and while tissues such as the liver can readily pathophysiology. store iron, the ability to excrete excess iron is poor. However, research on Brain-gut interactions in the pathogenesis and iron deficiency syndromes has uncovered of functional bowel disorders proteins originating from the liver and intestine that play a key role in the regulation Progress on functional GI disorders, such of iron absorption in the intestine. as IBS, can be attributed to a better charac- and were the first proteins to terization of the neurobiology of brain-gut be ascribed a role in iron absorption. Other interactions. The corticotropin-releasing proteins that underlie genetic disorders of iron factor (CRF) signaling pathway is the best transport, including HFE and hemojuvelin, described brain-gut circuit closely related to the might also be involved. Exploiting these pathogenesis of IBS. A CRF receptor antagonist discoveries will require a more integrated directed at normalizing a sensitized CRF approach to understanding intestinal system holds great promise for the treatment absorptive function than we can currently of IBS and cyclical vomiting syndrome. Another pursue, as well as a stronger understanding of major advance is the ability to image the living the cell types mediating absorption and their , making it possible to investigate response to stimuli. the role of genetic factors and receptor physi- ology on the pathophysiology of symptoms Neurophysiology and Motility and, thus, to provide a more precise endpoint to evaluate therapeutic interventions. Finally, Diversity in the structure and functional characterization of the 5-hydroxytryptamine organization of the enteric nervous system (5HT, also known as serotonin) receptor signaling system in the ENS may be important In addition to and smooth muscle cells, for the pathogenesis of a subset of IBS and normal functioning of the ENS requires partici- represents an important target for new thera- pation of the interstitial cells of Cajal (ICC), peutic approaches. glial cells, and enteroendocrine cells. It would not be possible to generate the motor program Stem cell technology for neuron stored in the ENS without patterned electrical regenerative therapy activity and synaptic connectivity provided by the ICC. These findings have implications Neural crest stem cells have been shown to in human physiology and pathophysiology as persist in the adult gut and to undergo changes abnormal networks of ICC have been reported in self-renewal. Cell-intrinsic differences

Research on the Basic Biology of the Digestive System 31 between stem cells from different regions cultivation-based methods for characterizing regulate the generation of neural diversity. the microflora, an approach that is both time- These exciting revelations suggest a new consuming and unreliable. A newly available mechanism for regeneration of intestinal molecular approach, the amplification and neurons after injury or disease. Further sequencing of bacterial 16S rDNA and possibly efforts should be directed toward identifying other highly conserved genes, makes it possible molecules and pathways that promote neural to characterize the intestinal microflora proliferation and differentiation in the gut more quickly and accurately. Researchers and/or guide the growth of enteric axons to can now assess the species composition and their targets. contributions of the microflora to causation or exacerbation of such health problems as IBD, GI tract in the regulation of satiety and colon cancer, and obesity. energy homeostasis Moving from species composition to Recognition of the pivotal role of gut hormones microflora function in homeostasis has opened up new therapeutic options for the treatment of obesity Taking a “census” of the bacteria that are and type 2 diabetes mellitus. Most importantly, present in the colon at any particular time is glucagon-like peptide-1 (GLP-1) and glucose- important, but the species identity of a microbe dependent insulinotropic polypeptide (GIP) does not usually reveal its metabolic potential. promote insulin biosynthesis and islet The metabolic potential of a microbial survival. GLP-1 also inhibits glucagon secretion population can now be assessed by genome and gastric emptying and induces satiety. The sequence analysis of cultivated members of the multiple actions of these gut hormones have microflora and metagenomic analysis of the been exploited to develop novel therapeutics entire bacterial population. In addition, a better in the treatment of diabetes and disorders of understanding of important bacterial products energy homeostasis. Rational manipulation such as enzymes, toxins, and hormone-like of the neuroendocrine pathways regulating compounds will make it possible to assess the appetite may be used to treat obesity. Another role of bacteria in intestinal diseases at the exciting finding is that gutmicroflora may molecular level. contribute to the pathophysiology of morbid obesity through differing capacities to harvest Composition and functions of colonic end- energy from the diet, which suggests that the product users: the archaea and gut microbiome may be a biomarker, a mediator, sulfate-reducing bacteria and/or a new therapeutic target for people suffering from obesity. Although research on the human colonic microflora has focused on the numerically Microbiology and Microbial-Host predominant populations and clinically Interactions significant minor populations, such as the Enterobacteriaceae and Enterococci, further Genomic analysis of the microbial studies have demonstrated the importance of a population of the human colon minor population that consists of fermentation end-product users, such as the methanogenic Testing hypotheses about the effects of archaea and sulfate-reducing bacteria. For the colonic microflora on human health their and energy needs, these microbes has been hampered by the need to rely on use hydrogen and carbon dioxide from the

32 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases fermentation of dietary polysaccharides and epithelial cells and take up organisms. This sulfate from fermentation of host-produced process is enhanced in epithelium exposed to polysaccharides, including and Toll-like receptor (TLR) ligands. Such limited mucopolysaccharides. Such characteristics commensal uptake leads to the production may increase the efficiency of the colonic of IgA antibodies, which function to reduce fermentation of polysaccharides, and their further bacterial uptake by coating organisms products, such as methane and sulfide, are likely and preventing colonization. It also leads to to have significant effects on the . the induction of regulatory T cells that control responses to commensal in the Horizontal gene transfer among human mucosal lumen and, thus, prevents the mucosal colonic bacteria microflora from inducinginflammation.

It is now known that bacteria in the colon Role of epithelial cells in mucosal host interact genetically and metabolically with defense and inflammation each other. Bacteria, unlike and other , do not experience species limitations Intestinal epithelial cells produce and are, therefore, able to transfer DNA and that initiate innate immune across species, genus, and phylum lines. These cell responses and, thus, set up a first line transfers can involve antibiotic resistance and of defense against the intrusion of harmful toxin genes that might contribute to intestinal organisms into the mucosa. Many of these disorders, but the extent or types of genes responses are induced by TLRs and nucleotide transferred is unknown. oligomerization domain-LRR receptors interacting with microbial components. Mucosal Immunology Epithelial cells also produce substances such as thymic stromal lymphopoietin (TSLP) that Role of the intestinal microflora in influenceDC function and, thereby, determine the maintenance of mucosal immune the nature of T cell differentiation that occurs homeostasis in relation to mucosal antigenic stimulation. Additionally, epithelial cells transport IgA via The mucosal immune system is unique in the polyimmunoglobulin receptor and IgG via that it lies in close proximity to an enormous the neonatal Fc receptor; in doing so, they carry consortium of commensal organisms that play antibacterial agents to the luminal surface and/ multiple roles in maintaining gut homeostasis, or move immunoglobulin/antigen complexes in including the prevention of colonization by a bi-directional manner across the epithelium. pathogens and the promotion of epithelial cell Finally, epithelial cells produce antibacterial repair following damage. These organisms are substances, including defensins (cryptins) and separated from mucosal lymphoid elements lectins that regulate the bacterial population by a single layer of epithelium and overlying in intestinal crypts and contribute to the that prevents wholesale entry of the development of IBD. bacteria. Nevertheless, it has been shown that commensal organisms do enter the The role of antigen-presenting cells mucosa via Peyer’s patches and are taken and other leukocytes in the mucosal up by dendritic cells (DC) in these lymphoid immune system structures. An additional mode of entry of commensal organisms is via DC in the lamina Researchers are defining the biology of propria, which extend processes between leukocytes and their role in innate (,

Research on the Basic Biology of the Digestive System 33 , and ) and adaptive Mucosal unresponsiveness (oral tolerance) (DC and ) immunity in numerous and development infectious, allergic, and inflammatory diseases of the gut. The DC is a key cellular player in Researchers have improved our understanding the mucosal immune response; as such, it of oral tolerance and the possible harnessing plays a role in mucosal host defense and in the of its underlying mechanisms to the therapy pathogenesis of IBD. Studies of the function of of mucosal inflammation. A significant step the mucosal DC revealed that these cells are, came with the demonstration that, while as a population, unique and contain several oral tolerance could be due to exposure of sub-populations with unique functional mucosal cells to high doses of antigen in the properties, such as directing the differentiation absence of adequate T cell co-stimulation, it of B cells into IgA-producing cells through the is more characteristically due to exposure of elaboration of differentiation factors, mucosal cells to low doses of antigen and the including BAFF and APRIL. Evidence has induction of regulatory T cells. Further work emerged that mucosal DC may be uniquely has established that the most important type involved in the induction of regulatory T cells of regulatory cell mediating oral tolerance is in the mucosa via the production of TGF-β, in the “natural” regulatory T cell that develops addition to the induction of Th17-producing in the and is defined by its expression cells via production of IL-6 and TGF-β. Thus, of surface markers, such as CD25, and a DC control the balance of effector cells and transcription factor known as FoxP3. Another regulatory cells at mucosal sites. regulatory cell that can develop in the mucosa and that may also mediate oral tolerance is Trafficking of mucosal cells to themucosal the Tr1 regulatory cell, which lacks high-level immune system FoxP3 expression and develops in relation to exogenous rather than self antigens. Factors Advances have been made in understanding that determine whether a mucosal antigenic how and why the mucosal immune system is will result in a positive immune unified by a cell circulation system that ensures effector response important for host defense or that cells generated within the inductive areas a negative regulatory T cell response important of the system—the Peyer’s patches and other for maintenance of an unresponsive state and lymphoid follicles—“home” back to the effector prevention of mucosal inflammation are still areas, the GI and other “diffuse” poorly understood, but may be due to the effects mucosal areas in other organs. Early studies of TLR ligands. focused on the role of integrin/integrin receptors,

particularly that of the α4β7 /MAdCAM-1 Mucosal vaccination combination, in gut homing. Newer work has established that regional expression of epithelial Researchers have expanded our knowledge chemokines in the small and large intestines of the factors controlling the generation of is indispensable in the homing process. A both humoral (IgA and IgG) and cellular major finding is that retinoic acid ( effector responses in the mucosal immune A) acting through its receptor (RAR) induces system. The follicle- and T cell-centered view IgA plasmablasts (T cells) to express homing of IgA-producing B cell differentiation has receptors for the gut with regulatory capacity. had to make room for a second pathway of It is now apparent that the traffic of cells in, IgA-producing B cell development, since it around, and outside of the mucosal immune is clear that IgA-producing B cells develop system is highly choreographed. in relation to exposure to components of the

34 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases commensal microflora in the absence of T cells, adjuvant, cholera toxin, has provided important CD40 ligand, or mucosal follicles. This pathway insights into the function of mucosal adjuvants. of IgA-producing B cell development could Thus, the picture that emerges is that mucosal be viewed as a more “innate” pathway, given adjuvants induce mucosal immunization, evidence that it occurs in response to innate rather than tolerance, because they activate receptors, such as TLR receptors, and may be DC to express surface molecules and cytokines triggered by T cell-independent non-protein that activate effector T cells, rather than antigens. Extensive study of the mucosal regulatory cells.

GOALS FOR RESEARCH 7

dEvEloPmEnt and administered for the treatment of diseases as diverse as and graft-versus-host Research Goal 1.1: Develop new technologies disease. Developing methods to identify, isolate, to isolate, characterize, cultivate, and manipulate and use ISCs for a wide variety of clinically relevant stem cells of the digestive system for research and tissue engineering applications would also have therapeutic applications. enormous implications for tissue repair and . The advances that have been Investigations into the origins and biology of made in MSC and ISC biology need to be extended intestinal stem cells (ISCs), mesenchymal stem into a better understanding of NSCs, which hold cells (MSCs), and, to a lesser extent, neural stem similar promise for neurologically derived diseases cells (NSCs) have evolved to a point where it of the gut. Finally, new stem cell technologies are is possible to envisage new therapies based on needed to test hypotheses concerning the role of stem cell biology. The identification of Lgr5, stem cells in cancer. for example, as a specific functional marker for ISCs and a detailed elucidation of the regional Objectives: factors that manage the ISC niche, such as those ß Develop new markers to identify different stem deriving from Notch and Wnt/β-catenin signaling cell populations of the digestive system. pathways, open the possibility for the development ß Develop new methods for isolation of stem cell of cell culture systems and, consequently, organ populations. ß Develop new methods for cultivation of stem engineering with clinically relevant applications. cell populations. Similarly, the recent illumination of the ways in ß Understand molecular pathways necessary for which MSCs can be differentiated into a variety lineage differentiation of stem cells. of intestinal cell types, such as neurons and ß Devise assays for characterization of specific endothelium, together with their unique biological stem cells and lineages. properties, has important ramifications. MSCs ß Devise animal models for development of are particularly appealing because of the relative potential therapeutic applications. ease by which they can be purified, manipulated,

7 Research Goals are numbered for ease of reference only; the numbers do not indicate prioritization of scientific topics.

Research on the Basic Biology of the Digestive System 35 GOALS FOR RESEARCH

Research Goal 1.2: Understand how particular The Wnt signaling pathway distinguishes the cell and tissue niches are generated and main- functions of crypt progenitors from those tained in the embryonic pancreas, liver, biliary tree, of differentiated villus epithelial cells, and its and digestive tract. dysregulation underlies development of colorectal cancer, the second leading cause of U.S. cancer An important challenge in development and deaths. Wnt signaling maintains proliferative homeostasis of all tissues is to understand how a capacity and lack of differentiation in crypts, limited number of signaling pathways are able to its absence permits differentiation in villi, and generate enormous diversity. This question is starting constitutive Wnt activity is responsible in large part to yield insights in the GI tract, where the roles of for dysregulated cell proliferation in colorectal and the Wnt, Notch, Hedgehog, BMP, Lgr5, and FGF some other GI tumors. pathways, among others, are being defined. Recent advances help delineate how these widely expressed Objectives: signaling pathways act in concert to generate tissue- ß Identify small molecules that interfere with distal and organ-specific structures and functions, and they steps in the Wnt signaling pathway for potential therapeutic use in cancer. establish the GI tract as an exceptional model system ß Identify other signals that impinge on β-catenin in which to study developmental mechanisms. stability and activity in colorectal epithelial cells and might serve as alternative targets for Objectives: pharmacologic therapy. ß Apply diverse model systems to investigate aspects

of gut development that are best approached through biochemical, genetic, and developmental Research Goal 1.4: Delineate specific signaling studies in Drosophila, chicken, and zebrafish. pathways, transcriptional regulation, and other ß Develop tools that permit accurately targeted interactions that mediate critical patterning events genetic studies in the gut of various animal in gut endoderm, which generate and maintain models, particularly a stable repertoire of its distinctive major derivatives (GI tract, liver, and transgenic animals that faithfully express Cre pancreas). recombinase, green fluorescence protein or beta- galactosidase reporter genes, or toxigenes, ideally Development and homeostasis of the developing in inducible forms. and adult digestive system represent the outcome ß Exploit the identification of intestinal epithelial of interactions of cells with one another and with stem cell markers to understand pathways their surrounding matrix. Signals that emanate from governing the development of the diverse these interactions drive tissue- and cell-specific epithelial cell types that populate the intestines, transcriptional programs, and their disturbance is stomach, pancreas, and biliary system. likely responsible for many disorders that are currently

treated empirically. Improved understanding of essential signaling mechanisms will enable rational, Research Goal 1.3: Exploit the advanced targeted therapy. understanding of Wnt-APC-β-catenin signaling in human epithelial function to develop new, effective Objectives: treatment strategies for colorectal cancer. (See also ß Delineate the relative contributions of specific Goal 4.11.) signaling pathways and transcriptional regulators

36 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases GOALS FOR RESEARCH

in gut development and learn how the Maintenance of intestinal homeostasis during intersection between extrinsic and cell-intrinsic development and adult life requires a proper signals drives development. balance among cell proliferation, apoptosis, ß Distinguish factors whose functions are restricted to and differentiation and involves interactions the developmental period from those that continue between epithelial and other cell types, to influence critical activities in adult organs. including mesenchymal cells such as fibroblasts. Understanding the molecular pathways that mediate normal intestinal growth and the response Research Goal 1.5: Translate advances from to injury and how extrinsic stimuli affect their laboratory research in gut development to identify activity is crucial for development of interventions disease mechanisms and therapeutic targets for diverse to maintain intestinal mass and functional GI disorders (e.g., congenital disorders, cancer). capacity. Intestinal adaptive growth is regulated by hormonal mediators, including GLP-2, IGF-1, In the long term, knowledge gained from and . Understanding the basic research must be translated into a clear mechanisms by which these and other hormones understanding of how specific developmental and affect gut growth is essential for developing homeostatic pathways are affected in individual GI therapies for individuals with intestinal failure, disorders. Such understanding will lead to strategies including patients who require parenteral nutrition. for rational intervention to prevent development or progression of disease. Objectives: ß Determine downstream mediators of growth Objectives: factor signaling that affect enterocyte prolif- ß Recognize the specific molecular defects eration and apoptosis, including the neural associated with particular congenital diseases or pathways that regulate hormone action. disorders and with tissue metaplasia and cancer, ß Understand cross-talk and synergism among especially Barrett’s esophagus, gastric intestinal intestinotrophic peptides, growth factors, metaplasia, intestine-type gastric cancer, nutrients, and other growth-promoting pancreatic in situ neoplasia and , molecules using animal models. and non-infectious hepatic disorders. ß Characterize the molecular basis of stromal- ß Integrate molecular databases (e.g., gene epithelial interactions in gut injury and repair expression, chromatin-immunoprecipitation, cis- to identify potential therapeutic targets using element analyses) with functional studies (e.g., transgenic models, microarrays, and proteomics. siRNA, genetically engineered animal models) to ß Develop strategies that leverage intestinotrophic identify new pathways and to better appreciate mediators in the treatment of short bowel underlying regulatory circuits. syndrome, IBD, intestinal damage induced by cancer , and ischemic injury. ß Develop novel methods of tissue engineering growtH and intEgrativE utilizing knowledge of the stem cell and its niche PHySiology to create functional neomucosa.

Research Goal 1.6: Define the physiologic basis for intestinal growth and adaptation and alterations with aging. (See also Goals 6.1 and 9.1.)

Research on the Basic Biology of the Digestive System 37 GOALS FOR RESEARCH

Research Goal 1.7: Define the physiologic basis ß Understand the mechanisms by which bariatric for energy balance, appetite, and satiety and their surgery leads to changes in body mass. roles in obesity. (See also Goal 1.10.) ß Develop therapeutic interventions to mimic the effects of on body mass. Disorders of energy balance, including obesity, ß Develop effective, peripherally active substances diabetes, and the metabolic syndrome, are for control of food intake and body weight, increasing in prevalence among adults and such as gut hormone-based therapies to target children, imposing severe personal and economic appetite circuits. costs on individuals and society. Experimental and ß Develop new assessment tools, technologies, empirical evidence, including patient outcomes and biomarkers to measure activity, nutrient after bariatric surgery, point to neuroendocrine intake, and energy balance. communication between the gut and the brain as a ß Define genetic risk alleles in order to discover crucial element in understanding the pathogenesis critical pathways involved in obesity and satiety. of these disorders. Integration of the function of ß Determine the mechanisms by which different the brain-gut axis with other sites that regulate macronutrients alter appetite and satiety. energy balance, including liver, pancreas, and ß Understand the interrelationship of basic , is essential to understanding the behavioral factors and brain-gut-nutrient axes pathophysiologic basis of metabolic disorders. in maintaining or changing body mass. Understanding how the presence of nutrients in the gut lumen is sensed by endocrine cells and nerves is critical for treatment of diseases in which Research Goal 1.8: Define the physiology of the signaling pathways are compromised and for neuroimmune pathways involved in inflammation. the development of therapeutic strategies for the regulation of food intake and body mass. Some gut Interactions between the nervous and immune hormones (CCK and PYY) regulate food intake via systems play important roles in normal and disease activation of neural substrates in the gut-brain axis. states in the GI tract. Research has provided new Long-term changes in the macronutrient content insights into neuroimmune relationships that may of the diet can alter the sensitivity of the gut-brain facilitate translation of basic science into new axis and may lead to lasting changes in body mass. therapies, particularly with regard to inflammatory diseases. An example is the cholinergic anti- Objectives: inflammatory pathway, which modulates release ß Assess the localization, expression, and of pro-inflammatory mediators in models of colitis, regulation of gut peptide receptors and ligands ischemia-reperfusion, postoperative ileus, and influencing food intake within the gut. pancreatitis. Neuronal signaling pathways in the ß Integrate physiology with peptidomic, proteomic, gut are also affected by inflammation. For example, metabolomic, or other technologies to identify pro-inflammatory cytokines can alter expression adipokines secreted by fat cells that influence gut and function of the mucosal serotonin transporter function and determine how signals originating (SERT), which affects neurohumoral signaling via from the gut affect adipose tissue biology, serotonergic pathways. Changes in function of metabolism, and the brain-gut axis. SERT and other neural pathways may therefore ß Assess the synergistic or inhibitory interactions underlie the altered motility, secretion, and between pre- and postprandially released gut sensation seen in these inflammatory gut disorders. peptides influencing food intake and metab- Better understanding of neuroimmune crosstalk in olism and examine the modulation of these GI inflammatory disease is warranted. interactions by dietary status and composition.

38 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases GOALS FOR RESEARCH

Objectives: Objectives: ß Address mechanisms responsible for neuroimmune ß Extend studies of candidate genes to examine protective and injurious states by combining selected absorptive and metabolic pathways expertise in neuroanatomy/neurophysiology, (e.g., cholesterol, , micronutrients) from immunology/inflammation, trauma, nutrition, and human populations using humanized knock-ins . of informative polymorphisms. ß Understand the cause and effect relationships ß Develop targeted approaches to obesity, between inflammation and altered neural function hyperlipidemia, and diabetes through testing and the functional implications of inflammation- candidate small molecule inhibitors of gene induced changes in neural signaling. function using mice and other models. ß Understand the role of nutrition in animal models, ß Integrate advances in developmental biology including lipid-based diets, in neurally mediated to understand regional differentiation of anti-inflammatory pathways. intestinal absorptive functions (e.g., ileal bile ß Use animal models of GI inflammatory acid transporter, duodenal iron absorption) and conditions to manipulate neural signaling possible plasticity. through pharmacological, electrical, or nutritional ß Develop selective siRNA and other tractable interventions; identify mechanisms of response and knock-down methodologies for widespread use effects on morbidity/mortality. in digestive/absorptive pathway interrogation. ß Develop therapeutics (drugs or devices) that are ß Understand the dialogue between host and based on neuroimmune pathways targeted to GI luminal bacteria and the signaling pathways disease (e.g., IBD) and that have GI involved. effects (e.g., shock, ischemia-reperfusion injury).

Research Goal 1.10: Identify critical pathways digEStion and mEtaBoliSm in murine and other in vivo models to develop targets for treatment of obesity and other disorders Research Goal 1.9: Develop a comprehensive of nutrient absorption and metabolism. (See also profile of intestinal genes that regulate mammalian Goal 1.7.) absorptive functions. A major challenge is to transition from hypothesis- Intestinal digestion, absorption, and metabolism directed, mechanistic studies of known pathways reflect the integrated functions of many into a reverse-genetic paradigm by which the pathways, most of which are incompletely etiology and complications of complex metabolic understood. For example, the single candidate disorders, such as diabetes and obesity, can be cholesterol transporter, NPC1L1, accounts for modeled. A complete understanding of the major most, but not all, cholesterol transport functions pathways that mediate macro- and micronutrient of the mammalian enterocyte, and there is an absorption should focus on a reverse genetics unanticipated redundancy with other pumps approach to transgenesis, using information from and membrane receptors. Newer murine models the human HapMap project to direct the study of are needed using double, triple, and other nutrient absorption and metabolism. combinatorial transgenic approaches (e.g., humanized knock-ins), coupled with targeted knock-out and knock-down technology.

Research on the Basic Biology of the Digestive System 39 GOALS FOR RESEARCH

Objectives: Research Goal 1.12: Define molecular ß Design targeted therapeutics based on informative pathways leading to differentiated absorptive and pathways that predict development of obesity, secretory functions. (See also Goal 9.2.) hyperlipidemia, and diabetes. ß Identify serum and tissue biomarkers that predict The commonalities between intestinal development alterations in pathways identified above. and tissue remodeling after injury are striking. Both ß Recognize the specific molecular defects require re-establishing equilibrium among the cell associated with nutrient malabsorption, including types that are required for transport functions that obesity, and defective or inappropriately increased are essential to life. Some of the essential molecular intestinal nutrient delivery. pathways promoting secretory cell types are known, ß Define mechanisms by which metabolic pathways but the routes to production of absorptive cell types interface with immune function. are much less clear.

Objectives: Nutrient and Fluid Absorption ß Integrate information on the role of cellular and and Secretion protein diversity in creating efficient absorptive and secretory function in healthy human and Research Goal 1.11: Define pathways that mouse tissues. regulate barrier function and transport function. ß Understand epithelial development and (See also Goal 9.2.) remodeling in response to injury, especially related to signals and pathways required to Researchers are defining the molecular create a balanced population of absorptive and components of the epithelial barrier and secretory cells. understanding more about their regulation. ß Apply and develop mouse models that allow The interplay between barrier function and net fine genetic mapping of qualitative trait loci transport in the gut is becoming evident. Barrier related to complex traits and multifactorial and transport dysfunction is common in multiple genetic disorders of absorption and secretion. intestinal disorders, and research in this area will ß Develop a proteome fingerprint of cell types improve understanding of health and disease and important to gut absorptive and secretory provide new therapeutic targets. functions and define the functional meaning of these profiles. Objectives: ß Examine the structure and function of proteins composing tight junctions, adherens junctions, and Research Goal 1.13: Develop means to other elements mediating the epithelial barrier. measure and manipulate epithelial function. ß Identify membrane transport proteins and intra- cellular chaperones of micronutrient and metal As we develop greater understanding about ion absorption (e.g., iron, , ). epithelial cell function and adaptation to different ß Expand use of non-mammalian models to conditions, either experimental or disease-based, studies of gut absorptive and secretory functions it is important to take advantage of advanced (e.g., zebrafish,C. elegans, Drosophila). models and techniques to translate key findings to the human condition and to benefit from broad, interdisciplinary approaches.

40 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Objectives: ß Characterize the molecular phenotypes of the ß Develop advanced mutant mouse models (e.g., different classes of enteric neurons (i.e., sensory, tissue-specific, knock-in, inducible , interneurons, and motor neurons). Develop humanized models, superior gene transfer unique biomarkers to allow evaluation of the methods for GI tissues) to study human proteins state of specific classes of enteric neurons during that mediate or regulate nutrient and fluid the development of GI motor disorders. absorption and secretion. ß Determine how enteric neurons function as a ß Understand the molecular and functional network to generate motor patterns, respond adaptation of individual epithelial cells of to luminal contents, produce stereotypical gut the intestine to challenge (e.g., surgery, reflexes, generate sensory signals, and adapt to inflammation,diabetes, obesity, or experimental conditions like inflammation or . manipulation). ß Understand the development of the ENS and ß Develop a conceptual basis and technical how adult neural stem cells might facilitate repair approaches for direct translation between of a defective ENS resulting from developmental human and animal studies of barrier, absorptive, defects or pathophysiologic damage. and secretory processes in living tissues ß Understand the role of glial cells in maintaining (e.g., imaging, molecular diagnostics, and the structure and integrity of enteric ganglia and therapeutics). in regulating the functions and health of enteric ß Foster interdisciplinary teams among clinical neurons. research, basic biomedical research, engineering, ß Understand how inflammatory cells and and computational fields. mediators influence neural activation and integration.

Neurophysiology and Motility Research Goal 1.15: Understand the structure, Research Goal 1.14: Define the basic cellular function, and regulatory mechanisms responsible and molecular mechanisms responsible for neural for motility in the GI tract. activation, integration, and regulation in the ENS. The ENS exerts control over smooth muscle cells The ENS regulates motor patterns in the GI tract. This to develop patterns of contractile responses, such division of the autonomic nervous system has been as , segmentation, tonic contraction, mapped extensively in a few animal models, but retroperistalsis, and others. ENS control is important mechanistic questions remain about the superimposed upon spontaneous activity of the organization and function of enteric neurons and glial musculature (so-called “myogenic” activity of cells. Additional studies characterizing neural reflexes, smooth muscle tissues) and contributions from neural plasticity, growth and development, and stem a variety of additional regulatory systems. A cell biology are needed to allow therapeutic control of more complete understanding is needed of the enteric neural function. interactions of the ENS with smooth muscle cells and the mechanisms responsible for regulation of Objectives: contractile behavior in order to develop targeted ß Understand the ionic and cellular regulatory therapies to improve motor function. mechanisms responsible for enteric nerve cell activation, synaptic transmission, integration, and motor pattern development.

Research on the Basic Biology of the Digestive System 41 GOALS FOR RESEARCH

Objectives: enteric neurons, glial cells, ICC, smooth muscle ß Understand the molecular signaling pathways cells, and enteroendocrine cells. Hence, functional responsible for generation of tonic and phasic and structural studies need to be performed with contractions in GI muscles and how these tools that allow dynamic visualization of the pathways are altered in pathophysiologic activity of the relevant cells in situ. Characterization conditions. of receptors, channels, and signal transduction ß Clearly define the role and mechanisms of systems unique to different cell types and how electro-mechanical and pharmaco-mechanical they interact with luminal events are critical to coupling in generating tone and phasic contrac- understanding how information is processed in the tions in GI muscles and the effects of sex coordination of motility, secretion, and absorption. hormones, inflammatory factors, and aging on these mechanisms. Objectives: ß Determine the molecular basis for electrical ß Investigate molecular and electrophysiological coupling between GI smooth muscle cells and characteristics of various ENS cellular between smooth muscle cells and interstitial components, which may be targets for new cells of Cajal (ICC) and the consequences of a developments to treat motility disorders. breakdown in electrical coupling on contractile ß Develop tools to visualize the state of activity of behavior. relevant cells in live tissues, organs, and systems. ß Determine the mechanisms and the role of ß Characterize alterations in gut-based 5HT calcium sensitization in response to neurotrans- and corticotropin-releasing factor (CRF) in mitters, hormones, and paracrine substances IBS and motility disorders, including genetic in GI contractile behavior and whether this polymorphisms affecting ligands, receptors, mechanism is altered by inflammation, sex transporters, enzymes, and/or signaling systems. hormones, or aging. ß Identify molecules and pathways that promote ß Determine the basis for spontaneous electrical proliferation and differentiation of enteric activity in smooth muscle cells and tissues and neurons and/or molecules responsible for the mechanisms for propagation of electrical directing enteric axons to their targets. activity in the generation of motor behavior of ß Define the molecular basis for chemo- and GI organs. mechano-receptors in the gut to ß Understand stretch-dependent mechanisms that ingested nutrient environment and gain better regulate the excitability of GI smooth muscles understanding about interactions between nutrient and contribute to patterns such as receptive and microbe-sensing mechanisms in relaxation, peristalsis, and gut stasis. the gut. ß Determine the effects of inflammatory mediators on the structure, function, and phenotype of GI smooth muscle cells and ICC. Research Goal 1.17: Characterize the neuromuscular phenotypes of human GI tissues.

Research Goal 1.16: Develop research Much has been learned in recent decades about the tools to investigate the structure and functional organization of the ENS and cellular mechanisms organization of the ENS. involved in generating normal gut motility patterns. Most information has come from studies of The multiple constituents of the ENS are laboratory animals. It is important to translate this characterized by a dynamic cross-talk between the information into studies of human GI muscles to

42 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases determine the neuromuscular phenotypes driving signaling and control of energy homeostasis, body normal human GI motility. Although access to weight, and various metabolic systems provides human samples is limited, surgery for GI conditions a new framework to study disorders of energy like cancer or obesity presents an opportunity for homeostasis. Pathophysiologic models coupled with studying human physiology. genomic analysis offer new opportunities to discover molecular mechanisms responsible for age-related Objectives: neuron degeneration and provide avenues to ß Understand the excitability and contractility reconstitute the ENS networks in diseased organs. mechanisms in human GI muscles. Translate knowledge obtained from animal models to Objectives: human physiology. ß Identify distinct brain circuits responsible for ß Understand the structure and function of the various gut functions and pain perception and human ENS. Determine which animal models characterize the signaling systems and receptors best simulate the integration and cellular within these neural circuits using PET ligand phenotypes of human enteric neurons. imaging in rodent models and humans with IBS ß Characterize motor innervation of the and functional dyspepsia. human muscularis and identify the major ß Develop contemporary techniques for probing neurotransmitters, the cells that are innervated genetic and proteomic changes that occur with by motor neurons, and the mechanisms of age. Establish the mechanism that maintains the post-junctional neural responses. integrity of the ENS and its capacity to respond to ß Define the receptors and signaling pathways that altered function or “plasticity” in adulthood and are involved in neural, hormonal, and paracrine old age. regulation of human GI muscle function. ß Investigate the cellular and molecular ß Develop methods of organ or cell culture that mechanisms of neural and endocrine bi- preserve the phenotypes of human muscle cell directional communication between the gut and components. Determine methods to culture the central nervous system (CNS) for regulation smooth muscle cells, ICC, enteric neurons, and of weight and metabolic function and the other cellular components without dramatic associated neurohumoral events. changes in the native phenotype. ß Develop suitable animal models to mimic diseases of the ENS.

Research Goal 1.18: Integrate cellular events in ENS with whole system physiology and translate Research Goal 1.19: Translate knowledge of the findings to pathophysiologic conditions. ENS in digestive health and disease into diagnostics and therapies for human disease. Normal functioning of the GI tract requires different components of the ENS to operate in Research on the pathophysiology of human motility unison, emphasizing the importance of identifying disorders needs to be aggressively translated into relationships in an organismal context. Advances the treatment of human diseases, given the progress in neurobiology of brain-gut interaction, together in research on functional GI disorders. This includes with availability of new neuroimaging modalities, advances in neuroimaging modalities to study brain- greatly enhance our ability to study functional GI gut interactions, efforts to unravel the complexity disorders and search for new therapeutic targets. of energy homeostasis systems, an understanding Recognition of the GI tract’s crucial role in satiety of some of the key neural circuits in the ENS,

Research on the Basic Biology of the Digestive System 43 GOALS FOR RESEARCH

and knowledge of developmental biology and intestinal microflora likely function as a separate, organogenesis, which allows for manipulation of yet integrated, organ within humans. A major neural stem cells in the bowel wall for replacement impediment to understanding this biomass is the lack therapy. of adequate methods to interrogate the composition of the intestinal microflora and its function. Evidence Objectives: now exists that the normal intestinal microflora ß Determine specific gene profiles in tissues that can directly influence and regulate the structure suffer ICC or neuron loss or in tissues in the and function of the normal intestine. The specific process of losing these elements and develop a properties and mechanisms by which the intestinal molecular test to detect these pathologic changes. microflora accomplish this are unknown, but ß Develop neural imaging techniques to correlate essential for both co-opting these mechanisms individual circuits identified with symptom for the development of new therapeutics and for production in IBS patients and establish understanding disease processes. correlation with distinct genotypes through such approaches as a genome-wide search for Objectives: polymorphisms and haplotypes. ß Undertake a metagenomic analysis of the micro- ß Develop neuron replacement therapy to guide the flora of healthy people and determine the extent growth of enteric axons to their targets as a therapy of person-to-person or diet-related variation. for neural degenerative disease of the ENS. ß Determine whether members of the major ß Characterize the molecular, cellular, and bacterial populations can transfer DNA to behavioral mechanisms that link changes of mammalian cells and test this hypothesis with in stored body fat to adaptive adjustments of vitro and in vivo models. feeding behaviors by defining the diverse blood- ß Develop a “humanized” mouse model of the borne and affective neural signals that transmit microflora in which germ-free mice are colonized information regarding nutrient status and energy with the human microbiome. stores to the brain where it is integrated with ß Obtain genome sequences of the gram-positive cognitive, visual, olfactory, and cues. anaerobic bacteria that account for over two- thirds of the colonic microflora, but about which virtually nothing is known, for use in interpreting microBiology and microBial-HoSt the metagenomic data and guiding biochemical intEractionS studies of the activities of these bacteria. ß Take a census of the methanogenic archaea and Research Goal 1.20: Determine the biologic sulfate-reducing bacteria found in the colons of activities of the microflora in healthy humans. (See healthy people. also Goals 5.3 and 9.3.) ß Determine whether bacterial enzymes, toxins, or hormone-like compounds affect intestinal The normal intestinal microflora consists of a total epithelial and non-epithelial cells. population that is at least 1012 microorganisms per ß Examine genome sequences from colonic gram of intestinal content. This microflora achieves bacteria to identify possible gene transfer events a mass that is equivalent to or exceeds the size of using advanced computational methods for several human visceral organs, but very little is known detecting such events. about it. Yet, the microflora are considered to be ß Understand the establishment of the microflora key to the biologic basis of numerous intestinal and in the neonate and the influence of non-intestinal conditions, including the maintenance feeding compared to commercial of physiologic homeostasis. As such, the normal formula feeding.

 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases GOALS FOR RESEARCH

Research Goal 1.21: Determine the ß Develop approaches to manipulating the mechanisms of host-microbial interactions that commensal microflora subpopulations to prevent are necessary to maintain health and contribute to or reverse infection and inflammation. pathological processes in disease. (See also Goals ß Design probiotics and prebiotics for maintenance 3.1, 5.3, and 9.3.) or restoration of healthy microflora. ß Determine whether the composition of the For the most part, mammals live in harmony with microflora or microbial gene expression has a role their enteric microbes and derive health benefits in conditions such as IBD, IBS, colon cancer, that are becoming increasingly recognized. This or obesity. relationship relies on a continuous exchange of ß Determine whether bacterial toxins or hormone- molecular and metabolic signals that are essential like compounds are involved in inflammatory for keeping a balance that is mutually beneficial intestinal diseases. to host and microbe. A major challenge is to ß Define the role of the normal microflora in better understand these complex interactions, maintenance of the mucosal immune system. as they are the underpinnings of both health and disease. Perturbations in host-microbial interactions can arise from numerous causes, mucoSal immunology including processes that affect human responses to microbes as well as changes in the composition Research Goal 1.22: Determine the role or behavior of the commensal microbes of epithelial cells in mucosal host defense and themselves. These disturbances may cause or be inflammation. a contributor to many diseases, including IBD, infectious gastrointestinal diseases, metabolic Epithelial cells are not passive participants in the syndrome/obesity, IBS, colon cancer, acid-peptic mucosal immune response but, on the contrary, play diseases, and autoimmune disorders. The insights active and perhaps key roles in the shaping and/or gained through further studies of host-microbial initiation of that response. interactions will promote the discovery of new ways to maintain health, as well as to treat and Objectives: prevent numerous common diseases. ß Identify factors that regulate the expression of innate immune receptors (e.g., TLR) in Objectives: epithelial cells and the effect of stimulation of ß Determine the interrelationship of digestion, these receptors on epithelial barrier function, microbes, and nutrients in normal health and and production, and digestive diseases. antimicrobial peptide production. ß Define the properties of the microflora that are ß Elucidate the effects of factors produced by associated with the maintenance and repair of epithelial cells that affect lamina propria DC the epithelial barrier. function and/or T cell differentiation, including ß Determine the mechanism by which the normal TSLP, IL-10, and TGF-β. intestinal microflora provides resistance against ß Generate mouse models expressing epithelial infectious invasion. cell-specific deletion of key genes involved in ß Determine why commensal organisms generally epithelial mucosal immune function and barrier elicit protective and anti-inflammatory responses function to define the function of these genes in in normal individuals, whereas pathogens elicit epithelial cell regulation of immune function. inflammation.

Research on the Basic Biology of the Digestive System 45 GOALS FOR RESEARCH

ß Characterize embryonic and adult stem cell ß Generate mice that lack key components of the differentiation into epithelial cells focusing gut homing apparatus and, thus, allow in-depth on the attainment of properties that relate to examination of gut homing mechanisms. epithelial immune function. ß Develop a systems approach to the study of and DC homing that integrates the many factors that affect this process. Research Goal 1.23: Understand the role of antigen-presenting cells in the mucosal immune system. Research Goal 1.25: Understand mucosal unresponsiveness (oral tolerance) and mucosal The DC is a key cellular player in the mucosal regulatory T cell development. immune response and, as such, plays a major role in mucosal host defense and mucosal The last decade has advanced the understanding of autoimmunity. mechanisms governing immune unresponsiveness to antigens in the mucosal environment, particularly Objectives: the function of regulatory cells that suppress ß Define the factors that influenceDC maturation responses to gut antigens (including commensal and function to mediate T cell effector and microflora and food antigens). The importance of regulatory functions within the mucosal these regulatory cells has become apparent in the environment. study of murine models of inflammation, in which ß Elucidate the function of DC TLR signaling with it was shown that lack of regulatory cell generation respect to positive and negative DC responses. leads to colonic inflammation and possibly toallergic ß Generate mouse models characterized by DC responses to food antigens as occurs in celiac disease dysfunction to study the role of DCs in mucosal and food . host defense and inflammation. Objectives: ß Determine the nature of the immunological Research Goal 1.24: Understand trafficking milieu of the mucosa in enhancing or retarding of mucosal cells to various parts of the mucosal the development of regulatory T cell functions, immune system. such as the synthesis of TGF-β, retinoic acid, IL-35, and IL-27. Researchers have begun to establish the cellular ß Understand the immunological mechanisms and molecular mechanisms that ensure that cells that underlie the development of food allergies generated within the inductive areas of the mucosal and develop methods to assess these allergies. immune system “home” back to the effector areas ß Elucidate the biology of regulatory T cells with of the system. relation to the function of FoxP3 and other intra- cellular factors that control regulatory cell function. Objectives: ß Develop gene therapy approaches to the ß Elucidate the factors that control chemokine- enhancement of regulatory T cell function to chemokine receptor interactions or other treat chronic inflammatory states. cell-cell interactions that contribute to mucosal traffic patterns.

46 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases GOALS FOR RESEARCH

Research Goal 1.26: Understand the Research Goal 1.27: Develop mucosal differentiation and function of mucosal lymphocytes vaccination strategies. and other immunologically active cells. A practical aspect of studying the induction of IgA The intestines are in a state of physiologic and other mucosal responses arises from the fact that inflammation that is presumed to be largely in the mucosal system is separated from the “systemic” response to the local milieu and, especially, to the immune system by the homing receptors that presence of the commensal microflora. This state mandate the traffic of cells originating in the inductive is important to mucosal defense against infections sites of the system to effector sites. This implies that and cancer but, when dysregulated, it can result in only mucosal immunization can effectively deal uncontrolled inflammation. with pathogenic invasion of the mucosa. This point is particularly relevant to the prevention of HIV Objectives: infection given evidence that the GI tract is a major ß Define the unique factors that mucosalize local site of initial HIV development and an important lymphocytes and other cell types (e.g., mast cells, reservoir of established HIV infection. mesenchymal cells) and, especially, the role of the commensal microflora. Objectives: ß Determine the site of induction and factors that ß Elucidate epithelial or stromal cell factors and regulate the development of mucosal effector cytokines involved in elaboration of IgA- (i.e., Th1, Th2, Th17, and NKT cell) and regulatory producing B cells. pathways in intestines. ß Understand IgG responses in the mucosal immune ß Investigate the effect of aging on these pathways. system and the neonatal Fc transport system. ß Develop new adjuvants that target particular aspects of the mucosal immune response. ß Develop effective vaccines for the prevention of major, epidemic, enteric viral infections.

MAJOR CHALLENGES AND STEPS of a coordinated system that would allow TO ACHIEVE the RESEARCH GOALS for the identification, characterization, and distribution of suitable mouse lines in a defined Animal models: The current range of animal (e.g., C57Bl/6) background, including conditional models for studying digestive diseases biology gain- and loss-of-function alleles that can be could be expanded by the development of tools induced in a temporally regulated manner; that permit targeted genetic studies in various and (2) centralized animal resources to act as animal models within specific tissues and cell a repository of useful models. Moreover, efforts types. Validation of specific promoters and/or to generate novel animal models of specific GI, minigenes that drive tissue- or segment-specific liver, and pancreatic disorders would accelerate gene expression in mouse and other relevant research on the molecular pathophysiology models (zebrafish,Xenopus , Drosophila) is of disease development. The success of required. Efforts to strengthen digestive translational research requires experimental disease research efforts across the scientific approaches in animal models that can be more community might include: (1) the establishment directly compared with human outcomes.

Research on the Basic Biology of the Digestive System 47 Therefore, equipment and chemical probes could algorithms, would enable researchers to detect be developed that permit parallel live tissue and determine the origin of mobile elements and analyses in the human and mouse intestinal to systematically screen such mobile elements to tract. The latter requires interdisciplinary ascertain what accessory genes (e.g., antibiotic research among digestive diseases researchers, resistance or toxin genes) are carried. chemists, and biomedical engineers. Progress in this field could be accelerated by Germ-free animal facilities: Many initiatives developing microarrays that represent genes proposed in this research plan involve the study on mobile elements found in the major groups of live experimental animals under conditions in of colonic bacteria and by making these broadly which the commensal microflora of the gut are available to the scientific community at a low strictly defined and controlled. Centralized germ- cost. Such methodologies could also focus on free facilities would provide qualified researchers defining the minor species of themicroflora with germ-free and/or microflora-defined mice for that have resisted cultivation to date. Finally, study under various conditions. If such facilities the development of new and better noninvasive could develop the capability of sending these mice means of quantitating the amount of energy to distant locations, research of this sort could derived from the colonic fermentation, the rate theoretically be conducted anywhere. of intestinal cell turnover, and the activity of the ENS would facilitate research on the effects Methods to characterize the microbiome: of the microflora in large groups of humans or It is critically important to develop basic animals. Noninvasive technologies, such as a tools to properly investigate and understand swallowed capsule or MRI (e.g., to detect the fate the composition of the normal intestinal of swallowed dyes), to monitor changes in the microflora. As part of this effort, there is a need composition and activities of the microflora in to collect and organize a curated database to different segments of the GI tract are priorities accommodate large amounts of 16S rDNA and for development. Resources being developed metagenomic sequence data and to develop under the auspices of the Human Microbiome advanced bioinformatic methods for analyzing Project, an initiative of the NIH Roadmap for these data. In addition, microarrays need to be Medical Research, will be critically important developed that contain rDNA sequences from for meeting these challenges. all of the major human colonic species for rapid characterization of the species composition of Cell lines relevant to the digestive system: the colonic population. Primary cells derived from humans and animal models with defined attributes would enable More sophisticated analysis of sequence data, in vitro studies to characterize the signaling especially metagenomic sequence data, to pathways and secretory potential of a large deduce the known and undiscovered activities variety of cell types. Important cell lines to be of the intestinal microbiome will require defined and established are those related to the collaboration between experts in microbial intestinal epithelial (and mesenchymal) stem physiology and bioinformatics. Improvements cells, as well as native intestinal epithelial cell in microarray technologies could eliminate and DC lines. To do so, it will be important to the need for any amplification step (i.e., direct develop better cell-specific markers. In addition, sampling of community DNA in the case of innovative techniques are required for the the 16S rDNA array and of RNA in the case long-term maintenance of cells in culture under of metagenomic microarrays). Advanced circumstances in which the cells do not undergo computational approaches, such as codon usage major changes in their characteristics. Moreover,

48 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases central facilities to acquire and maintain these proteome fingerprint of cell types important cells for distribution would be helpful. to various digestive disease processes, as well as to digestive development, physiology, and Bioinformatics: GI research would benefit immunology, in mouse and humans would from the development and implementation promote research progress. This could be of novel genomic and proteomic approaches augmented by the generation of large national and bioinformatics databases. Investments data and tissue banks for the application of to develop computational biologists and modern genomic and proteomic technologies. bioinformatics infrastructure and to foster interdisciplinary research between GI Translation of genetic findings into physiologists (including immunologists and understanding human digestive disease: bacteriologists) and computational biologists Integration of genetic discovery research with would strengthen the field. Mammalian models studies to understand the function of newly that provide systems biology resolution would discovered genes is required to translate basic allow integration of information from molecular research into opportunities to improve human regulation research directly into studies health. Academia-industry dialogue could be defining organismal impact without the need encouraged to expand our understanding of to create new models. For example, it might digestive diseases in human populations. be possible to identify the role of a protein The development and coordination of regional without creating a tissue-specific conditional and national databases with appropriate knock-out or transgene. Centers could be serum, DNA, and tissue biobanking would developed for cell type-specific protein profiling provide crucial resources for the entire and disease state profiling with standardized research community. procedures and outcomes. Development of a

Research on the Basic Biology of the Digestive System 49 Fluorescent and phase-contrast images of mouse stomach indicating the presence of a protein called Kit, which is found in a particular cell type involved in gastrointestinal motility known as interstitial cells of Cajal.

Image courtesy of Dr. Kenton Sanders. Used with permission of the American Physiological Society. Am J Physiol Cell Physiol 279:C529-C539, 2000.

0 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Functional gastrointestinal disorders and motility disorders

Summary oF rESEarcH goalS

Functional gastrointestinal (GI) disorders and motility disorders, such as irritable bowel syndrome (IBS), functional dyspepsia, and gastroesophageal reflux disease (GERD), take a significant toll on the health and well-being of many Americans. The Commission offers several research goals designed to improve our understanding of normal motility and secretory activities of the GI tract, discover the physiologic changes that lead to disease, and develop more effective therapies to prevent, treat, or reverse these disorders. Research efforts are needed on the numerous systems and processes that may be impaired in functional GI and motility disorders, including brain-gut interactions, the enteric nervous system, interstitial cells of Cajal and smooth muscle cells, pain and sensory mechanisms, the gut mucosa and musculature, the intestinal microflora, and immune and inflammatory responses. It is important to define how factors such as genetic differences, age, sex, and gender influence a person’s susceptibility to these disorders. Many individuals with diabetes develop GI motility disorders, such as gastroparesis and constipation. As the rate of diabetes continues to rise in the U.S., research on how diabetes affects the GI tract is increasingly important. Ultimately, research to discover the basic mechanisms of disease must be translated into new technologies, pharmacological therapies, and behavioral strategies to effectively treat all patients afflicted with functional GI and motility disorders.

Functional Gastrointestinal Disorders and Motility Disorders  INTRODUCTION AND BACKGROUND a slightly lower prevalence of diarrhea. In a burden of illness study published in 2002, Functional GI and motility disorders represent GERD, IBS, and chronic diarrhea had the common conditions seen by both primary highest prevalence rates and each had a very care specialists and gastroenterologists. A significant economic burden. With respect functional GI disorder is characterized clini- to claims data, abdominal pain is the most cally by a constellation of symptoms that may frequent GI symptom reported and results in include physiologic dysfunction such as altered significant healthcare utilization. Thus, GI GI motility and secretion, visceral hypersensi- motility and sensory abnormalities result in tivity, and brain-gut dysregulation. A motility disorders of high prevalence and constitute disorder is defined by observable disturbances frequent reasons for consultation. in neuromuscular functioning of the enteric nervous system (ENS) and the muscularis. Additionally, there is a series of motility There is significant overlap between what have disorders whose prevalence is lower, but the been traditionally categorized as functional impact of these disorders can be deleterious, disorders or motility disorders. In order to devastating, or life-threatening. These condi- develop a more visionary research effort, some tions include gastroparesis (slow emptying investigators believe that a new paradigm of the stomach), chronic intestinal pseudoob- should be established that moves away from struction, Hirschsprung’s disease, , the traditional compartmentalization of and fecal incontinence. The first four appear functional and motility disorders and develops to result from significant neuromuscular a more encompassing and biomechanistic impairment, leading to impaired ability to framework for these diseases. The traditional maintain hydration, nutrition, appropriate delineation of “functional” versus “organic” digestion, and from the gut. Fecal in this area of clinical medicine is likely to be incontinence constitutes a significant social unsustainable as the pathophysiology of these burden that may result in stigma, social diseases is discovered. isolation, and impaired quality of life, particu- larly for women. These conditions have significant impact on the American public because of their high Pathogenesis and natural history: prevalence and negative effects on quality Functional GI and motility disorders are of life, high direct and indirect costs, and the heterogeneous and defined largely by devastating consequences of the rare forms of symptoms or pathophysiologic changes. The these diseases. Irrespective of the definition etiologies of these disorders are not well or criteria applied to study their prevalence, understood. Research into the pathologic both IBS and functional dyspepsia show mechanisms and etiology of functional GI prevalence rates ranging from 6-30 percent of and motility disorders is expected to lead to the U.S. population. GERD, which results from major changes in the current classifications of disordered competence of the motor functions these disorders. Dependent upon the disorder, of the lower esophageal sphincter, affects 14-29 presentation may range from altered GI motor percent of people at least weekly and results in activity, including abnormal sphincter function costs of $8 billion or more annually. and/or transit (resulting in nausea, vomiting, Some patients require surgery which may be loss of appetite, constipation, or diarrhea), to unsuccessful in at least 10 percent of patients. a state of heightened visceral nociception (the Estimates for prevalence of constipation range perception of pain, discomfort, or bloating in from 3-19 percent of the U.S. population with the gut), or a combination of both motor and

 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases sensory symptoms. Factors that predispose remedies, and both have significant labeled patients to develop hypersensitivity may be safety warnings. Some data suggest a role both peripherally and centrally mediated. for anti-depressants in the treatment of IBS, In animal models and human diseases, gut although confirmatory, contemporary efficacy inflammation, gutinjury, altered gut mucosal studies have either not been performed or did immunity, psychiatric conditions, or psycho- not demonstrate efficacy in the intent-to-treat social factors all may modulate the reciprocal cohort. Antibiotics and probiotics may relieve pathways between the brain and gut, inducing bloating, but have not been fully established as states of hypersensitivity. Factors leading to treatments for other IBS symptoms. abnormal motor function may include reduced inhibitory neuronal activity, heightened cholin- Whether antibiotic prophylaxis will be a ergic neural activity, loss of pacemaker cells, successful strategy to prevent post-infectious or abnormal responses to endocrine mediators. IBS remains to be determined. Several classes The specific alteration in mediators is known of agents are in development for various for only a few disorders. functional and motility-related disorders aimed at addressing either altered states of motility Current means of control, cure, and/or or visceral hypersensitivity: corticotropin- prevention: The range of therapeutic agents releasing factor (CRF) antagonists, novel available for the treatment of functional GI agonists, NK antagonists, atypical disorders and motility disorders remains benzodiazepines, kappa-opiate agonists, mu- limited, with no agents that can cure or prevent opiate antagonists/agonists, chloride channel the disorders. The lack of agents that can cure openers/closers, beta agonists, guanylate or prevent these disorders reflects the very cyclase C agonists, other agents that act on limited understanding of their pathologic the serotonin system, cannabinoids, and mast mechanisms and etiology and, perhaps, an cell stabilizers. The range of medications being inappropriate grouping of patients for testing of tested reflects the complexity of the control therapies. Agents that generically speed or slow mechanisms, the redundancy of the neurohor- motility, or tighten or loosen sphincter tone, monal mediators, and the need to more clearly are used across a variety of disease states. As a understand the pivotal mechanisms under- class, dopamine antagonists and 5HT4 agonists pinning the development of these syndromes. function as gastroprokinetic-type agents (i.e., drugs that stimulate stomach emptying), while To fully understand these diseases and develop anticholinergics and calcium channel blockers safe and effective therapies, a major research are (i.e., drugs that suppress effort is underway to address the basic mecha- smooth muscle activity). Erythromycin has nisms underlying the neuromuscular control, been found to have only limited use as a including studies of extrinsic and intrinsic gastroprokinetic, even though it has a degree nerves that control the gut, pacemaker cells of motilin-like binding activity. Alosetron is and muscular mechanisms, the development of a 5HT3 receptor antagonist indicated for the the neuromuscular apparatus, the molecular treatment of severe, diarrhea-predominant, and genetic disorders associated with human female IBS patients; tegaserod, a 5HT4 disease, the afferent mechanisms that convey receptor agonist, is indicated for female, sensations of pain and nausea to the conscious constipation-predominant IBS patients. brain, and the reflex pathways that periph- However, these agents are only indicated erally modulate those sensations to protect the for female patients with severe disease conscious brain. In addition, the social, psycho- unresponsive to first line symptomatic logical, and behavioral aspects of these diseases

Functional Gastrointestinal Disorders and Motility Disorders 53 are being explored, and researchers are looking the immune system has led to the recognition for new ways to enhance disease management that the arbitrary division of gut disorders as by improving the delivery of , inflammatory disorders or functional disorders optimizing the doctor-patient relationship, may be misleading. Immune activation and developing medications and devices that appears to be common in GI motility disorders, can restore normal function or provide means although a lack of common terminology and to support use of the gut for nutrition, normal methodology has limited comparisons between bowel function, and continence. sub-groups. Immune methodology, including genetic studies, is now widely available and can be applied to the field of GImotility disorders. RECENT RESEARCH ADVANCES Abnormal physiology may be triggered by an insult or perturbation, such as an infection, The brain-gut axis and neurohormonal and result in long-term alterations in ENS control of motor and sensory functions or CNS responses to subsequent stimuli. of the GI tract Prospective evaluations of post-infectious IBS have shown that up to 20 percent of individuals Specific advances include an understanding with bacterial may develop that serotonin activates intrinsic and extrinsic symptoms of IBS or dyspepsia. Infection has primary afferent neurons to promote peristaltic been shown in epidemiological studies to and secretory reflexes and to modulate sensory confer an increased risk for development of signaling in the brain-gut axis. Identification IBS. Predictive factors show two important of different serotonin receptor subtypes in features relative to the pathogenesis of this the GI tract has allowed development of disorder: (a) association of mucosal inflam- drugs to modulate GI motility, secretion, and mation and altered mucosal immunity; and (b) sensation. Polymorphisms in the promoter association of psychosocial disturbance at time region of the gene encoding the serotonin of infection. Mast cells and enterochromaffin reuptake transporter (SERT) may have a cells have been found to be markers of mucosal role in patients with diarrhea-predominant immune activation in IBS in humans and IBS. This new understanding of GI functional in animal models. Mast cell is a mechanisms has facilitated the development common finding in mucosal from the of novel pharmacologic treatments for GI large intestine of IBS patients. Changes in the motility disorders, functional GI disorders, mucosal immune system may also increase the and obesity. Treatments and potential new excitability of neurons involved in local reflexes targets for intervention include: 5HT3 receptor and central pathways in response to food antagonists, 5HT4 receptor agonists, CRF antigens and chemical stimuli. Such insults antagonists, ghrelin, neurokinins, nitric oxide to the intestine may increase mucosal perme- and other gas neurotransmitters, mu-opioid ability, rendering the mucosa more susceptible receptor modulation, cannabinoids, and mast to luminal antigens and aggravating the cell stabilizers. inflammatory state.

Role of the immune system and inflam- Altered bacterial flora infunctional GI mation in GI diseases disorders (including post-infectious IBS)

A growing understanding of the nature and Luminal bacterial microflora can affect mucosal complexity of the interactions between the inflammation and immune function leading to central nervous system (CNS), the ENS, and neural sensitization. A rapidly growing body

54 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases of evidence suggests that important signaling of the brain-in-the-gut, including reduction in pathways exist between the microflora and the population of inhibitory motor neurons to the gut (including signaling to enterochro- the musculature. Extreme loss of inhibitory maffin, immune, and nerve cells), which may motor neurons or disconnection of motor contribute to normal homeostasis and may be neurons with post-junctional cells manifests altered in disease states such as inflammatory as disinhibitory motor disease, such as bowel diseases (IBD), IBS, and possibly obesity. achalasia or pylorospasm in the smooth muscle Research on the effects of “good” and “bad” sphincters, and hyperactive, disorganized bacteria on mucosal immune function suggests contractile behavior of intestinal muscle the possible benefits ofprobiotic bacteria cells, which results in pseudoobstruction. to either prevent or treat these conditions. Detection of anti-enteric neuronal antibodies Further studies are needed to determine the in the serum of patients with early symptoms patient subset that might be most responsive to of a functional GI or motility disorder may this type of treatment. be a useful diagnostic test for inflammatory enteric neuropathy, including paraneoplastic Interaction of stress circuitry and disease associated with small cell lung cancer. gut function Other diseases, including diabetes, cause an autoimmune-mediated visceral neuropathy Researchers have shown that dysregulation probably affecting extrinsic and intrinsic of stress circuitry can affect gut function. nerves. Evidence for this link includes: (a) increased corticotropin-releasing hormone (CRH) Neural stem cells (neural crest stem cells) and adrenocorticotropic hormone (ACTH) in the gut reactivity to stress and increased motor and pain responses to CRH, which can be blocked Researchers have discovered that neural crest by CRH antagonists; (b) increased mucosal stem cells persist in the gut after birth. Stem immune activation; (c) stress-associated cells from other sources also show potential disruption of intestinal mucosal barrier for giving rise to functional neurons in the GI function (i.e., increased membrane perme- tract. The field of directedstem is ability, mast cell activation, and mucosal developing and holds some promise for future inflammation, which may lead to visceral clinical applications. sensitization); and (d) altered limbic system (i.e., anterior cingulate ) reactivity to Development of the ENS visceral signals leading to increased pain response in functional GI disorders. The latter The molecular genetics of multiple endocrine is enhanced by stress. neoplasia type 2B and Hirschsprung’s disease—prototypic disorders characterized Immune response to the enteric by gross and/or microscopic of the nervous system ENS and associated dysmotility—have been identified. Intercellular signaling pathways Autoimmune responses targeted to neuronal involved in enteric neurodevelopment have elements of the ENS can underlie a variety of been characterized. Mutations associated with conditions from IBS-like symptoms to chronic abnormalities of neuroenteric development pseudoobstruction. Enteric inflammatory are known in animal models and in a spectrum neuropathy disrupts the integrative functions of human disease processes, including:

Functional Gastrointestinal Disorders and Motility Disorders 55 and genetic knock-out models that have pointed have been developed to treat these disorders to the molecular mechanisms responsible for GI with evidence from randomized, controlled neuromuscular function and disease. trials that these treatments are effective for constipation and fecal incontinence. Improved imaging or diagnostic techniques Evaluation of drugs with the potential for therapy in functional bowel disorders Better, more quantitative, and, in many cases, noninvasive techniques have been Many different methods are available to developed to understand normal and abnormal evaluate potential new to determine esophago-gastric motility (e.g., high-resolution whether they provide benefit in the treatment manometry, impedance manometry and of IBS. Great strides have been made in impedance pH, SPECT, and MRI), to assess establishing a consistent design to study new GI motility (e.g., stable isotope breath tests, potential medicines for the treatment of IBS, SmartPill), and to evaluate involvement of including: how to collect data, how long to study the CNS (e.g., PET, MRI, magnetoencephalo- treatments, and what parameters to monitor graphy) in functional GI disorders. to demonstrate efficacy based on valid psycho- metrics and construct validity. By having a Mechanisms of obstructed and strong, consistent way to test new medicines, fecal incontinence it is more likely that the results of studies, whether positive or negative, are accurate and, and fecal incontinence if positive, will be regarded as acceptable by present a significant burden for patients. New regulatory agencies. techniques, including the use of biofeedback,

Goals for research 8

Research Goal 2.1: Understand the molecular serve as pacemakers and neural mediators in the gut, and cellular events that yield normal motility, may lead to new insights for methods to prevent sensory behavior, and integration between motility loss of these cells or compensate for their function in and secretory activity in the GI tract and the functional GI disorders. pathophysiology of functional GI disorders and motility disorders. Objectives: ß Develop cell-specific markers for each cellular In order to identify and properly repair defects component involved in gut neuromuscular associated with GI disease, it is critical to develop a function and visceral sensation. detailed understanding of the normal functioning of ß Characterize differences in gene expression in the gut and the brain-gut axis. Research to elucidate specific cell populations in health and disease. major signaling pathways that perform the sensory ß Develop biomarkers that can be used to and neuromuscular functions of the GI organs or the assess the health and function of specific excitability and contractile mechanisms in these organs cellular components. is warranted. Studies of the physiology of ICC, which

8 Research Goals are numbered for ease of reference only; the numbers do not indicate prioritization of scientific topics.

Functional Gastrointestinal Disorders and Motility Disorders 57 Goals for for Research Research

ß Determine why ICC are lost in many motility The nervous system of the gut is highly complex disorders and how to restore this population and involves multiple cellular components, such as of cells. efferent and afferent neurons, interneurons, and . A primary goal for research on functional GI disorders is to distinguish the role of these nervous Research Goal 2.2: Understand the development system cells in health and disease. Interactions of the GI tract and brain-gut interactions and between the intrinsic and extrinsic nervous systems determine how the aging process and differences in and alterations in neural targets and effectors sex and gender affect gut development and function in functional GI and motility disorders are also and brain-gut interactions. (See also Goal 9.7.) incompletely understood.

The burden of many functional GI disorders varies Objectives: by age and sex/gender. Studying the effects of ß Define the role of the vagal homeostatic system genetics, sex, hormonal status, and aging on the (e.g., vagal anti-nociception, vagal anti- development and function of cells and integrated inflammatory reflex). behaviors of cells in the GI tract will provide a more ß Determine the role of the sympathetic nervous complete understanding of normal GI function system in regulating gut and sphincter function. throughout the lifespan. This information combined ß Define how neural integration is accomplished with the identification of developmental or gender- in peripheral neurons and how GI sensation specific factors that predispose the gut to motor or integrates with central pain pathways. functional pathologies will help researchers design ß Understand the degree to which cognitive targeted therapies to prevent, treat, or reverse these and emotional processes participate in the disorders in vulnerable populations. generation and/or symptoms of chronic functional GI disorders. Objectives: ß Develop a comprehensive picture of how genetics and environmental factors affect Research Goal 2.4: Understand the immune development and maintenance of normal functions of the muscularis, integration between function of the GI tract and the brain-gut axis. mucosal and muscle immune responses, and ß Determine why women are disproportionately how inflammatory processes contribute to the affected by functional GI and motility disorders. pathogenesis and maintenance of functional GI ß Determine how hormonal status affects the and motility disorders. neuromuscular apparatus of the GI tract and how it might predispose the gut to abnormal The GI tract is a key point of interaction between motility or abnormal sensation. the immune system and the environment. Many ß Learn the mechanisms of fecal incontinence and GI motility disorders are associated with immune develop means of prevention and treatment. activation. Progress in this field requires a deeper understanding of the immune function of the gut and how it relates to the development of functional Research Goal 2.3: Understand the components GI and motility disorders. Understanding the role of and functional interactions of the peripheral inflammatory responses of resident and infiltrating (autonomic and enteric) and central nervous immune cells (innate and adaptive immune systems in normal physiology and in functional GI responses) and characterizing specific populations and motility disorders. of immune cells that either reside in or infiltrate gut tissue are important research goals. Interactions

58 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Goals for Research

of the immune system with intrinsic and extrinsic how sensory input from the gut integrates with neurons and other cells might also influence the information from other viscera and with activity of onset of disease. Clinical testing is warranted to the CNS. Progress could be made by defining how evaluate the effectiveness of mast cell stabilizers the CNS or processes sensory information and mediators on GI symptoms. With increased differently in animal models and in patients with knowledge about immune function in the gut, functional GI and motility disorders. researchers will be able to design new therapies to blunt the effects of inflammation-inducedmotility Objectives: disorders and their systemic consequences (e.g., ß Clarify -afferent nerve systemic inflammatory response syndrome, barrier terminal interactions. What are the mechanisms function failure). of afferent nerve activation and sensitization in the GI tract? Objectives: ß Characterize the integration between visceral ß Define mucosal functions (immune, barrier, nociceptive pathways and motor pathways. sensing/taste) and the role of inflammation. ß Determine the mechanisms for GI sensation and ß Determine the interactions of pro-inflammatory perception of sensation and how the gain of immune cells and neural cells in diseases of the visceral sensory pathways increases in functional ENS and hypersensitivity. GI disorders. ß Characterize the inflammatory responses to ß Develop new agents to reduce nociception and various insults to the GI tract and develop the undesirable visceral sensation. means to disrupt or reverse these responses. ß Characterize the sites and mechanisms of ß Characterize the effects of probiotics on central processing of inappropriate sensation in mucosal-immune interactions. the GI tract in normal individuals and patients ß Determine the efficacy ofantibiotics in with functional GI disorders. prevention and treatment of post-infectious and idiopathic IBS. Research Goal 2.6: Understand the noxious visceral signaling causing nausea and vomiting Research Goal 2.5: Understand peripheral and related to gastric neuro-electrical and/or motor central pain and sensory pathways and how these dysfunction and the bi-directional brain-gut pathways are affected in functional GI and motility interactions. disorders. Gastroparesis provides an archetypal disease for Pain is one of the most debilitating symptoms of investigative inquiry. Chronic vomiting, a debilitating functional GI and motility disorders. In order to and socially isolating digestive symptom, creates develop better treatments to combat pain, it is potentially life-threatening disruptions in fluid and important to identify the ion channels expressed in electrolyte homeostasis and compromises nutritional nociceptive nerves and to search for specific blockers status. Chronic nausea remains a significant hidden of these channels that might relieve chronic visceral disability. Nausea and vomiting usually occur in pain. Understanding how generator potentials tandem and overlay with other GI symptoms as well develop in nociceptive neurons and how to block or as presenting in numerous digestive diseases. More reverse the processes that lead to hypersensitivity effective treatments for nausea and vomiting would of afferent neurons will also help researchers design improve quality of life and physical functioning in new therapies. Another key issue is to determine a vast array of illnesses. A paucity of research exists

Functional Gastrointestinal Disorders and Motility Disorders 59 Goals for for Research Research

for defining peripheral noxious signaling ofnausea The human microflora include the diverse and vomiting related to primary GI motor/sensory collection of bacteria and other microbes inhabiting disturbances. Understanding normal electrophysi- the digestive tract; little is known about the role of ologic motor function would assist in unraveling the microflora in health and disease. An important the perturbed sensory signaling in postprandial research focus is to understand how luminal factors nausea and vomiting, as well as the nausea and such as the gut microflora,inflammation, diet, or vomiting of severe gastric motor derangements as infection influence the relative types, density, and are found in gastroparesis. More research related functions of enteroendocrine cells—hormone- to the autonomic nervous system and circadian producing cells found throughout the lining of patterns may provide interesting insights and lead the digestive tract. The impact of the intestinal to the development of interventions that impact the microflora on bi-directionalbrain-gut communi- brain-gut-humoral axis. cation and the interactions between a patient’s genotype and that of the microflora in their gut are Objectives: key issues. Understanding these processes could ß Clarify electrophysiologic normality and provide new insights into the triggers of symptoms abnormalities, especially tachyarrhythmias, and symptom differences (e.g., constipation, and their contribution to noxious signaling of diarrhea, or bloating) in functional GI and motility nausea/vomiting. disorders. ß Characterize function and dysfunction of gastric and small bowel ICC and the presence, absence, Objectives: and relative functional phenotypes of ICC in ß Characterize the impact of the intestinal micro- full thickness tissue biopsies and other GI tissue flora on bi-directionalbrain-gut communication. samples to identify abnormalities in slow wave ß Characterize the effects of stress, diet, and generation, frequency regulation, propagation, infections on gut microflora. and neural regulation. ß Determine the relationship between a patient’s ß Characterize the impact of diet, anxiety, and genotype and the microbiome. sleep disruption on modulation of nausea and ß Determine the impact of alterations in the vomiting. content of the microflora on GI function and ß Use animal models to understand the role of sensation. cytokines and to increase understanding of afferent signaling in nausea and vomiting. ß Determine the modulating effect of therapeutic Research Goal 2.8: Use information from interventions on CNS function using evidence studies of animal models and cellular physiology from functional MRI (fMRI) studies. to understand the integrated function of the ß Understand the role of esophageal, gastric, and musculature and the intrinsic and extrinsic nervous small bowel sensory and mechanoreceptors (in systems. nerves, ICC, and smooth muscle cells) in the generation of nausea and vomiting. Animal models that mimic human disease or that recapitulate specific pathways, structures, or behaviors contributing to human disease are Research Goal 2.7: Understand the role of the critical tools for understanding the relationships microflora infunctional GI disorders and motility between cellular defects and organ- or system- disorders. level symptoms in functional GI and motility disorders. These models allow researchers to

60 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Goals for Research

address important questions that cannot be studied Research Goal 2.9: Characterize the factors in in human patients, such as how cellular elements diabetes that lead to the development of functional intersect to yield tissue- or organ-level behaviors GI and motility diseases. or how nerves regulate the barrier function of the mucosa. Research is also warranted to define Patients with long-standing diabetes are prone to changes in the ENS that cause inappropriate motor development of GI motility disorders at all levels of patterns in the gut and the contribution of the CNS the GI tract from the esophagus to the anorectum. to altered function in the ENS. With animal models, These problems are increasing as obesity and cases researchers can study how the ENS stores motor of type 2 diabetes increase. GI complications of patterns and potentially translate that knowledge diabetes may be complex, severe, and substantially into new strategies to selectively change an decrease quality of life. Common complaints inappropriate motor pattern to one that would include: dysphasia, premature satiety, esophageal be beneficial to patients with functional GI and reflux,constipation, pain, nausea, vomiting, and motility disorders. diarrhea. GI motility defects have traditionally been attributed to the development of autonomic Objectives: neuropathy; however, recent findings suggest that ß Develop conceptual and/or quantitative models additional cellular defects may also contribute to GI to demonstrate how various pathophysiologic complications. Although few studies have addressed inputs—such as stress, altered gut microflora, or the changes in visceral sensory function that neuroendocrine dysfunction—might influence occur in diabetes, abnormalities in pain perception motor patterns, integration between motility thresholds, vagal activity, and evoked brain poten- and secretion, and visceral sensation. tials suggest that diabetes-related neural changes ß Use animal models to determine the role of may be both peripheral and within the CNS. infection, metabolic disease, stress, and sex on GI phenotype, neural integration, afferent Objectives: nerve sensitivity, neuro-immune responses, ß Characterize changes in neural chemical coding neuro-muscular transmission, pacemaking, in the ENS and functional consequences of and integration of information between the identifiable neuropathies associated with long- peripheral and central nervous systems. standing diabetes. ß Use selective genetic models to determine the ß Determine non-neuronal cells that are role of specific signaling pathways, neurotrans- functionally impaired by loss or suboptimal mitter systems, and immune responses in insulin/IGF-1 signaling. normal and pathophysiologic states. ß Determine whether dysfunction or loss of ß Develop noninvasive, in vivo research neuronal and non-neuronal cells in diabetes diagnostic tools suitable for small animal results from poor glycemic control, loss of or research. These tools (e.g., small animal MRI, defective insulin/IGF-1 signaling, or other ultrasound, PET, SQUID, breath tests) could unidentified defects inherent to the complica- be used to screen for GI phenotypes in genetic tions of diabetes. mutants and also to test pharmacological ß Develop novel biomarkers to evaluate damage agents. to specific cellular compartments or sub-classes ß Develop and utilize better data mining tools for of enteric neurons in diabetes. the screening and comparison of large-scale ß Characterize specificmotility and functional expression data in animal disease models. defects in animal models of both type 1 and ß Use animal models to develop new biomarkers type 2 diabetes. of gut health and function.

Functional Gastrointestinal Disorders and Motility Disorders 61 Goals for for Research Research

Research Goal 2.10: Determine how genotype Growing evidence suggests that food plays an contributes to or predisposes patients to the devel- important role in the pathogenesis of GI symptoms. opment of functional GI and motility disorders. It is possible that specific food constituents have primary effects on gut function and sensation, A primary goal in digestive diseases research is to rather than an intermediary effect through gut understand the role of genetics in the etiology, microflora. Abnormal immunologic responses to manifestations, prognosis, and therapeutic responses food might be linked to the development of defects of patients with functional GI and motility disorders. in gut function and sensation and other symptoms These diseases are multifactorial and likely to be of functional GI and motility disorders. polygenic in nature. Interactions between genes and the environment also contribute to the complexities Objectives: of these disorders in unknown ways. By identifying ß Utilize animal models to study the influence of specific genetic polymorphisms or gene-environment specific food components on gut function and interactions that predict disease or correlate with gut sensation. intermediate phenotypes (e.g., sensitivity to pain, GI ß Develop animal models of food allergies. transit, autonomic parameters, activity and sensory ß Determine the effects of specific food processing in the CNS), it might be possible to design components and food allergies on early intervention strategies to prevent or blunt the populations and on the development of full clinical syndromes of functional function of afferent nerve function. GI and motility disorders in genetically at-risk people. ß Develop patient tests to identify food allergies This may also allow targeting of therapeutics to the or hypersensitivity to food components. population most likely to receive benefit. ß Identify and critically evaluate dietary treatments for functional GI disorders. Objectives: ß Determine the role of gut taste receptors on GI ß Develop genetic epidemiological studies to function. discover common genetic factors that predispose patients to develop functional GI or motility disorders. Research Goal 2.12: Develop new technologies ß Develop and validate endophenotypes and therapeutic approaches to effectively treat (intermediate hereditary characteristics between patients with functional GI and motility disorders. the disease and the genotype) as a means of clarifying links between the genotype and the Progress in alleviating functional GI and motility complicated phenotypes of functional GI and disorders would be spurred by the development and motility disorders. routine application of innovative, state-of-the-art ß Utilize validated endophenotypes to clarify technologies for diagnosis and treatment. Imaging classification and diagnosis of functional GI and approaches in both animal models and human motility disorders and to foster the development subjects could accelerate early clinical testing and of animal models. evaluation of new therapeutics and help researchers ß Utilize a pharmacogenetic approach to predict identify the most promising candidates to test which patients might respond to specific therapies. in clinical trials. Improvements in noninvasive electrical recording of the GI tract for diagnostic purposes would facilitate diagnosis of patients Research Goal 2.11: Determine the role of food with functional GI disorders. The development of in the development of functional GI and motility simple, noninvasive GI motility testing modalities disorders. (See also Goal 8.8) that can be applied on a large scale would improve

62 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Goals for Research

our understanding of the prevalence of these Research Goal 2.13: Evaluate therapeutic disorders in the general population. Research on the outcomes and the impact of doctor/patient causes and mechanisms of neural hypersensitivity interactions to determine effective treatments for in relation to other functional pain disorders functional GI and motility disorders. could make it possible to apply more general strategies to functional GI disorders. Functional GI and motility disorders result from a Finally, a major advance in treating functional GI complex and poorly understood combination of disorders might come from improving small bowel physiologic and psychological factors that can give transplantation so that this procedure becomes as rise to a variety of symptoms. Patient-oriented routine as . research could be pursued to define the underlying causes of the diverse symptoms of GI motility Research into the biology of stem cells will facilitate disorders. Clinical trials can be designed to compare the development of stem cell-based treatments the relative clinical effectiveness and cost- of gut disorders where smooth muscle cells, effectiveness of standard treatment approaches ICC, or enteric neurons are reduced, absent, to innovative disease management approaches or malfunctioning as in fecal incontinence, that involve novel pharmacological compounds pseudoobstruction, gastroparesis, and constipation. and non-pharmacological strategies (e.g., disease By using stem cell biology technology and tissue education, cognitive behavioral therapy, physician engineering approaches, it may be possible to repair education, web-based telemedicine approaches). or replace damaged cellular or tissue components. The impact of standardized physician training programs on GI patient outcomes and cost is Objectives: another important research question. ß Develop and evaluate new therapeutic pharmaceutical agents for treatment of Objectives: functional GI and motility disorders. ß Develop innovative ways to optimize ß Develop new devices or applications of novel healthcare delivery systems for GI disorders to stimulus regimes to target vagal nerve function. enhance outcomes and reduce costs. ß Develop new devices, surgical techniques, or ß Determine the elements of the healthcare tissue replacement approaches to enhance provider-patient relationship that will improve fecal continence. healthcare outcomes, such as interview ß Develop and validate standard measures techniques, relationship-centered care, emotion for health outcomes research (e.g., primary management, and placebo administration. treatment endpoints, health-related quality of ß Determine the effect of healthcare provider life, psychosocial assessment, health behaviors, education and training to enhance the such as healthcare utilization and decreased daily provider-patient relationship on clinical function, and costs). outcomes, including patient satisfaction, ß Standardize behavioral treatments to make adherence to treatment, improved symptoms, them generalizable to a broader population. quality of life, and healthcare costs. ß Identify GI tract-specificstem cell populations ß Conduct randomized, controlled trials of and develop techniques to regenerate specific stress management and relaxation methods, cell populations or tissues. hypnotherapy, and cognitive behavioral therapy in pediatric and adult populations.

Functional Gastrointestinal Disorders and Motility Disorders 63 MAJOR CHALLENGES AND STEPS knock-outs in GI cells. Techniques to effectively TO ACHIEVE the RESEARCH GOALS turn on and off expression of specific genes in adult animals would also facilitate research in Methods to study the diversity of GI cells: this area. Functional GI and motility disorders are complex and result from functional defects in a Technologies to study the influence of wide variety of cell types. At present, few well- the nervous system: Visceral pain is among defined animal models have been developed, the most debilitating symptoms of many GI and human tissues and cells are infrequently disorders. Better understanding of nociception, available, except from biopsies. A better under- inappropriate sensation, and sensitization standing is required of the many cell types that of afferent neurons and pathways would produce normal GI motility and appropriate enhance the development of new therapies levels of GI sensation, including muscle cells, to combat pain. Development of techniques intrinsic and extrinsic neurons, glial cells, ICC, to discriminate between different classes of and a variety of immune cells (both resident afferent nerve terminals and to clearly identify and recruited). The development of innovative nociceptive nerve terminals in living tissues techniques to isolate and identify specific types should be encouraged. Dynamic imaging of cells from healthy and diseased gut samples techniques would provide a means to study would promote progress across the field. Such the behavior of afferent nerve terminals in techniques would allow determination of the lamina propria and muscularis layers of specific changes in cellular phenotype that the GI tract. A more detailed understanding might occur during development of a disease of the mechanisms of generator potentials in process and facilitate the use of state-of-the-art nociceptive neurons would strengthen the field. technologies, such as genomic and proteomic analyses. A better understanding of the integration between the brain-gut axis in pathophysiologic Moreover, phenotypes of GI cells involved in conditions and pathways of communication motility and neural responses are not conserved between intrinsic and extrinsic neurons adequately in cell cultures because the gut is required. Research in this area could be microenvironment is important to establish and enhanced by the design of: better recording maintain specific cellular phenotypes. Smooth methods to measure activity of the autonomic muscle cells, for example, change radically when nervous system in conscious experimental removed from the natural microenvironment animals and to correlate neural activity with and can no longer be considered to represent a motility; techniques to record from the CNS in smooth muscle phenotype within a short period conscious experimental animals (e.g., fMRI or in culture. Higher standards for verification PET) that correlate activity with peripheral of phenotypic fidelity of cultured cells need to neural activity and motility; and methods be established. A shortage of culture models to probe the links between disorders of GI makes large-scale genomic and cell biology function (e.g., constipation and diarrhea) and studies very difficult. The development of new pain and discomfort in the gut. technologies is required in order to manipulate genetic expression of GI cell types while the Systems biology approaches: The devel- cells are still in their native environment. opment of models or a conceptual framework For example, enhanced spatial and temporal that unifies disciplines related to morphology targeting of transgenic methodologies would and cell biology, including anatomy, histology, enable researchers to create better, cell-specific histochemistry, molecular biology, and pathway

64 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases analysis, with topics relevant to physiology, of what can and cannot be extrapolated from such as functions of cells and integration of animal models to humans will help refine cellular function in tissues and organs, would animal models. Complementary studies enhance research to understand how cellular on human GI tissues and cells will enable and sub-cellular events summate to produce researchers to determine whether cellular and whole system physiology and how cellular molecular components and pathways identified dysfunction contributes to pathophysiologic in animal models are relevant to human behaviors. Assembling and comparing physiology and pathophysiology. The devel- databases from gene and protein expression opment of better techniques for monitoring studies of specific GI cell types in normal and GI function, autonomic function, and brain pathophysiologic states might begin to reveal function in genetically altered animals would the many micro-defects that can lead to whole- increase efficiency for phenotyping animal organ or system dysfunction. Understanding models. In addition, genetic screens to specifi- specific changes in gene and protein expression cally identify defective GI motility, autonomic that are common to specific functional GI and CNS phenotypes, and the inactivation of and motility disorders might provide insights genes linked to defective motility phenotypes in into biomarkers that can characterize these animals would promote progress. diseases more definitively. More sophisticated dynamic imaging techniques would facilitate New model systems are required to determine understanding of interactions between GI cells the functional effects of variations in candidate and how discrete cellular and sub-cellular genes that are reputed to alter motor and defects in genetically altered animal models sensory functions, as well as somatization, contribute to function and dysfunction of resulting in GI tract symptoms or diseases tissues and organs. (i.e., testing of functional genomics). Further research is also required to develop techniques Integrative biology approaches: Studies that evaluate GI motility in model organisms, of how environmental factors and life experi- such as zebrafish or mice, in order to screen ences affect gut function (e.g., how stress, genes that are linked to altered bowel function. psychosocial co-morbidities, and impairment Testing human polymorphisms in vertebrate of CNS-ENS regulatory systems affect the models would shed light on the consequences gut) will help to elucidate their impact on the of genetic variation, in terms of motor and/or morphology, function, and integration of GI sensory function. cells and tissues. Many integrative studies are difficult or unethical to perform on human Standardized molecular definitions, patients. Thus, improved animal models for biomarkers, and clinical treatments: functional GI and motility disorders would Progress in understanding and treating enable researchers to explore the cause- GI disorders would be accelerated by the and-effect relationship between suspected development of consensus clinical descrip- pathologic factors and the development of tions of functional GI disorders and motility symptoms and disease. While it would be disorders. Such descriptions would, in turn, extremely useful to have animal models that enable the establishment of multicenter closely mimic human diseases, much can also patient registries and tissue/reagent banks. be learned from animals that manifest partial These resources would facilitate research phenotypes (i.e., that capture specific morpho- on the physiologic responses of human GI logic, pathophysiologic, or behavioral aspects tissues from comprehensively phenotyped of human disease). A clearer understanding and genotyped individuals with functional GI

Functional Gastrointestinal Disorders and Motility Disorders 65 and motility disorders to help determine the A consortium approach would be beneficial pathophysiology and mechanisms of these because it would provide the large numbers disorders. Moreover, a systems biology approach of samples and controls that are required for would allow patient biosamples to be analyzed informative studies of these disorders. for genetic similarities and differences and to be used to develop biomarkers that might be used Innovative transplantation techniques: to further categorize and diagnose functional GI Better transplantation therapies are required, disorders and motility disorders. possibly based on stem cell therapies and tissue engineering. To address this challenge, Similarly, standardization of clinical assess- more information is needed about the stem ments and treatments of functional GI disorders cell populations in the GI tract and how and motility disorders across patient popula- to manipulate the phenotypes of stem cell tions and clinical research centers would be an derivatives. Improvements in transplantation important step toward enabling researchers techniques would allow GI transplantation to directly compare data and outcomes. to become as common as with other organ Standardization of techniques and methods of systems. The development of innovative analysis of brain imaging, assays for mucosal techniques to restore function within regions cytokines and neuropeptides, and reporting of GI organs through tissue engineering could of clinical outcomes in treatment trials would also be encouraged. all strengthen the research field as a whole.

66 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Functional Gastrointestinal Disorders and Motility Disorders 67 Electron micrograph of enterotoxigenic Escherichia coli contacting microvilli on the surface of epithelial cells within pig small intestine. These organisms are a major cause of human diarrheal disease worldwide.

Image courtesy of Dr. Harley Moon. Used with permission of The University of Chicago Press as reprinted from J Infect Dis. 1977. 136:124-129. © 1977 by the University of Chicago. All rights reserved.

 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases infections of the gastrointestinal tract

Summary oF rESEarcH goalS

Gastrointestinal (GI) infections can be caused by many types of microbes, including bacteria, viruses, protozoa, and helminths. The Commission recommends research goals that are focused on identifying disease-causing microbes, understanding what distinguishes those organisms from the normal microflora of the human GI tract, and using that knowledge to develop safe, effective therapies to prevent and treat intestinal infections. Developing new, more efficient diagnostic methods to identify specific organisms is critical for rapid treatment and for understanding the epidemiology of infectious disease outbreaks.

Research is needed to develop better treatments, including vaccines, that address both the infectious agents themselves, as well as the long-term effects of GI infection in the gut and other organ systems throughout the body. The human GI tract is colonized from birth with microorganisms that are essential for normal growth and digestive function. Research on the nature and function of the human microflora could suggest strategies to manipulate these beneficial microbes to combat pathogenic organisms.

Collectively, achievement of these goals has the potential to reduce the public health burden of infectious diseases in the U.S. and globally.

Infections of the Gastrointestinal Tract  INTRODUCTION AND BACKGROUND 2005 Nobel Prize in Physiology or Medicine was awarded (additional information on this Diarrheal disease is a major cause of morbidity, advance and related future research goals with incidence rates ranging from two illnesses appear in the chapter on Diseases of the per person per year in developed countries to Stomach and Small Intestine). In addition, 12 or more in developing countries. Intestinal animal studies suggest that some species in infections continue to exact an unacceptable the intestinal microflora might precipitate toll on childhood and adult well-being. This or perpetuate inflammatory bowel diseases is particularly true in the developing world (IBD) and contribute to extraintestinal where diarrhea has significant morbidity manifestations of autoimmune diseases. Most and mortality, especially when accompanied recently, dramatic studies indicate that the by . In industrialized countries, microflora living in the intestine can have a deaths from diarrheal diseases are uncommon, profound impact on overall health and non- but the morbidity and economic costs diarrheal diseases, such as obesity. associated with intestinal infections remain substantial and the burden of lost productivity Intestinal infections pose multiple might exceed $19 billion per year. In recent challenges. First, illness etiologies vary by years, developed countries in North America geography, requiring investigative strategies and Europe have experienced outbreaks of that are location-appropriate. Second, a highly toxic and antibiotic-resistant strain accurate diagnoses are often thwarted by of the bacteria Clostridium difficile linked the polymicrobial nature of stool and the to overuse of antibiotic therapy. Although limitations of current diagnostic tools. common enteric infections are not the highest Third, host-microbe interactions show priority for efforts directed at bioterrorism, great variability related to host-microbial research advances in infectious diseases of the genetics and host-microbial cross-talk. digestive system could help to provide better Enteric infections in people with the acquired solutions to the problem, in the event that immunodeficiency syndrome (AIDS), immune enteric infectious agents might be used in the suppression due to organ transplants, and future as agents of bioterrorism. other immune disorders also require unique approaches. Viruses, bacteria, and parasites cause protean illnesses, including acute watery diarrhea, Diarrhea continues to burden communities bloody diarrhea, persistent diarrhea, chronic that lack clean water, safe food, and acceptable diarrhea, and infection. The waste management. Underlying problems etiologies of many intestinal infections remain often relate to development, economic, and unknown. GI infections and alterations in political issues, which are difficult for the enteric microflora might also be related to medical community to address effectively. functional GI disorders, either directly or as However, the consequences of these illnesses post-infectious phenomena such as irritable diminish the ability of communities to bowel syndrome (IBS). Research is also counteract these non-medical challenges. uncovering the role of specific microbes in GI Globally, poor growth is the most important inflammation, such as the ground-breaking risk factor for childhood morbidity and studies linking the bacteria Helicobacter mortality, and many children in resource-poor pylori to and peptic ulcer disease— regions have abnormal small bowel structure conditions that were not previously thought and function, including crypt hyperplasia, to have an infectious cause—for which the villus stunting, hypercellular lamina propria,

0 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases decreased mucosal surface area, and increased exemplifies a pathogen with enhanced virulence intestinal permeability. These changes are in nosocomial (hospital or other healthcare plausibly caused by environmental exposure to unit) and community settings, particularly contaminated food and water, but the roles of those located in North America and Europe. specific components of the microflora remain to These organisms cause increased morbidity and be determined. mortality, and development of more effective strategies to prevent and treat C. difficile A number of promising advances in disease should be considered a high priority. vaccination strategies have been made, including the development of effective rotaviral Bacterial-host interactions vaccines. Additional vaccines and other novel preventive strategies are critically needed to There has long been recognition that bacterial- reduce the impact and burden of GI infections. host interactions are a two-way street, and These approaches are highly effective and that organisms respond to their milieu. provide dramatic return on investment. However, specific communication mechanisms, particularly those that up-regulate virulence factors and induce injury, are poorly RECENT RESEARCH ADVANCES elucidated. Similarly, bacteria in the gut can be modulated by the host, as exemplified by Emergence of novel agents of GI illnesses adrenergic signaling to enteropathogenic E. coli (EPEC). This work suggests that such Using the best technologies, many enteric a mechanism might be exploited to diminish infections remain undiagnosed. Escherichia host injury. coli is the most common facultative in the human gut, and most E. coli are non- Environment-pathogen-host interconnection pathogenic. However, a subset of E. coli has acquired sufficient virulence traits to The inter-epidemic reservoir of Vibrio cholerae cause severe human disease. Recent data is a major source of human illness. A strong demonstrate the likely etiologic role of inverse association between bacteriophage enteroaggregative E. coli (EAEC) in traveler’s “blooms” and V. cholerae presence in water in diarrhea, persistent childhood diarrhea, and Bangladesh illustrates the complex interplay even as a cause of emergency department between the environment, bacterial control visits in North America. By identifying such elements (e.g., bacteriophages and V. cholerae), agents, it is now possible to develop diagnostic, and reservoirs that serve as vehicles to transmit prevention, treatment, and complication this pathogen to humans. The intersection mitigation strategies. The recognition that between reservoirs and hosts will need to be EAEC and other diarrheagenic E. coli cause addressed to control enteric pathogens. disease in multiple human populations with diverse syndromes exemplifies the challenge Mechanisms of viral pathogenesis of pathogen discovery when the agent closely resembles harmless or even beneficial Novel mechanisms have been discovered microflora (e.g., commensal E. coli). for GI viral pathogenesis, including viral enterotoxins and host-pathogen interactions, Emergence of enhanced virulent strains such as new ways in which viral pathogens counteract the innate host response. Genetic Well-established pathogens have acquired polymorphisms have been shown to increase new virulence traits. Clostridium difficile

Infections of the Gastrointestinal Tract 71 non-immune mediated resistance to infection vaccines for hookworm and schistosomiasis, (host susceptibility) and may affect immunity as well as identification of promisingvaccine to viral infections and vaccines. New animal candidates for amebiasis—so-called “anti- models have led to better understanding poverty vaccine development”—are significant of pathogenesis and immunity, as well as advances with worldwide impact. opportunities for preclinical testing of new vaccines and therapeutics. Such models Mechanisms of probiotic activity include rotavirus (RV)-induced biliary atresia, RV-associated intussusception, RV-induced The demonstration that immune and epithelial sterilizing mucosal immunity in mice, human cells can communicate and subsequently RV-induced disease in rats with recurrent discriminate between different microbial infection, and norovirus-induced disease in species has extended the known mechanism(s) mice and piglets. of action of probiotics. Probiotics may exert their disease-modifying effects through one or Susceptibility to infection or disease more mechanisms that include: competitive exclusion, antimicrobial activity, enhanced Data have emerged linking gut disease epithelial barrier activity through tight junction susceptibility to changes in gut physiology. modification and mucus production, and Alterations in barrier function may give rise stimulation of anti-inflammatory mucosal and to IBD and/or other autoimmune diseases, and systemic effects through a number of complex acute infectious inflammatory diarrhea may probiotic-epithelial-immune cell interactions. predispose to IBS. Susceptibility to infection is also related to alterations in gut immunology The progressive unravelling of these and/or host genetics; for example, IL8 gene mechanisms of action has led to new polymorphisms modify clinical diarrheal credence for the use of probiotics in clinical disease severity. medicine. Level 1 evidence now exists for the therapeutic use of probiotics in infectious Antiviral and intestinal parasite diarrhea in children, recurrent C. difficile- vaccines and therapies induced infections, and post-operative . Level 2 and 3 evidence is emerging The development and licensing of two new for the use of probiotics in other GI infections, rotavirus vaccines is an important advance prevention of post-operative bacterial in the prevention of rotavirus infections, the translocation, IBS, and in both ulcerative leading cause of severe diarrheal disease and colitis and Crohn’s disease. Nevertheless, it dehydration in infants and young children in is clear that not all probiotic bacteria have both industrialized and developing countries. similar actions or therapeutic effects. Genome sequencing, protein expression, and crystal structures of key proteins and viral Extraintestinal consequences of GI infection structures inform targets for the development of new therapeutics, as well as a molecular Campylobacter jejuni is a fairly common cause understanding of strain diversity that may of bacterial enteric infection. This organism be critical for vaccine development. Virus-like is found worldwide and transmitted through particles are being studied as safe and efficient the food supply, most typically poultry. A immunogens and as tools for environmental and small subset of infected patients will develop epidemiological studies. Likewise, development Guillain-Barre syndrome, a severe, debilitating, and early-stage clinical testing of recombinant potentially lethal ascending neurologic

72 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases paralysis. The chief pathogenic mechanism is Bacterial communities in the gut as believed to be induction of antibodies to the determinants of non-infectious diseases C. jejuni lipopolysaccharide, which also react against peripheral and central nervous system The human intestinal microflora are gangliosides. This is an example of autoimmune metabolically, genetically, and antigenically molecular mimicry following a GI infection diverse. Germ-free mice are protected against and exemplifies the role of host defense (i.e., obesity when consuming conventional antibody induction) leading to host injury. It is Western-style diets rich in and fat, an important paradigm applicable to a panel while colonized animals are not. The gut of additional pathogens. GI virus infection microflora are an important component of is not confined to the gut, but can spread our metabolic output, and metagenomic and extraintestinally; for example, rotavirus causes biochemical studies demonstrate the critical viremia in children and all animal models roles of the microflora in harvesting dietary tested. Extraintestinal spread may be a general calories and transferring energy in the form characteristic of human gastroenteritis viruses; of calories to the vertebrate host. The relative this property was not previously appreciated abundance of the two major bacterial intra- based on studies with animal caliciviruses intestinal divisions—Bacteroidetes and and . Firmicutes—is a potential determinant of host adiposity. Alterations in this microflora offer Long-term impact of enteric the opportunity for significant influence of parasitic infection extraintestinal health, such as obesity risk— an avenue that has not yet been adequately The long-term impact on growth and cognitive explored. Many methanogenic archaea—a function of repeated or persistent enteric group of prokaryotic and single-celled parasitic infections (e.g., protozoa, helminths) microorganisms similar to bacteria—are found has been recognized. These studies highlight in the digestive tracts of humans. The role of how enteric parasitic diseases contribute to this community in human digestive health and long-term economic and intellectual losses in disease is not well established. resource-poor countries with implications for global development.

Infections of the Gastrointestinal Tract 73 GOALS FOR R ESEARCH 9

Research Goal 3.1: Elucidate the etiology, In addition, genotypic variability among pathogens epidemiology, and pathogenesis and improve renders some organisms more virulent than others, diagnostic tests for intestinal infections. (See also and the specific determinants of pathogenicity are Goals 1.21 and 9.3.) often poorly understood for infectious agents.

In the U.S., an estimated 20-40 million episodes Objectives: of diarrhea occur annually in children younger ß Understand the pathogenic mechanisms than 5 years of age, and diarrheal illnesses used by viruses, parasites, and bacteria continue to be a burden for older children and in causing intestinal infection, including adults. Approximately 13 percent of all pediatric genotypic variability in known and putative hospitalizations in the U.S. in this age group are enteropathogens. for diarrheal disease. Worldwide, the number of ß Understand how microorganisms interact with childhood deaths from diarrhea is higher than 2.5 their environment to reach critical numbers million per year. capable of human infection and to express pathogenic factors in the intestine. Knowledge of diarrheal disease has increased ß Conduct epidemiologic investigations using remarkably during the past few decades. Numerous modern tools to define infectious etiologies, bacterial pathogens and an increasing number establish the incidence of known and novel of viral pathogens have been demonstrated to etiologic agents of diarrheal disease, and cause diarrhea. However, the etiology of diarrheal characterize the health impact of acute and disease in both developing and developed countries persistent enteric infection in distinct subgroups is unknown for 25-40 percent of all illnesses. of hosts, including normal and immune- Although diarrhea morbidity and mortality are compromised populations (e.g., solid organ largely related to fluid and nutrient losses, the transplant, marrow transplant, specific etiology of intestinal infection is critically patients). important for designing science-based prevention ß Develop new point-of-care diagnostics to easily and control mechanisms, especially vaccination. and rapidly detect known microbial enteric pathogens. Classically, assigning pathogenicity to an organism ß Discern correlates of protective immunity for has depended on identification of candidate enteric infections. pathogens more frequently in infected individuals ß Develop animal models to study the effects of than in asymptomatic controls. This approach manipulating the microbial community in the gut. is less informative when considering organisms that contain a repertoire of virulence loci. This is especially pertinent in view of recent data Research Goal 3.2: Improve the prevention that bacterial chromosomes are mosaics, made and treatment of intestinal infections. up of horizontally acquired elements that may contain genes that are not necessarily found in all Provision of clean water and sanitary food are pathogens. Clearly, designation of an organism important worldwide strategies to prevent enteric as a pathogen now requires considerably more infection. However, preventing enteric illness by sophisticated microbial and genomic sampling and improved hygiene is currently impractical in most statistical analyses than have been used previously. developing countries. For this reason, vaccination

9 Research Goals are numbered for ease of reference only; the numbers do not indicate prioritization of scientific topics.

74 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Goals for Research

against the most important GI infections has or ribotype 027. The recent experience with been aggressively pursued. A new generation of C. difficile serves to emphasize the need for better enteric vaccines based on either live or nonliving diagnostics, early recognition, improved methods antigens delivered orally or by injection is in the to manage severe disease and relapsing disease, early phases of evaluation. However, considerable and greater attention to infection control and technical barriers need to be overcome related to restraint in the administration of antibiotic therapy. the large number of pathogens capable of causing In addition, emerging antibiotic resistance in other disease and the requirement to induce immunity GI pathogens and pathogens that use the GI tract that is effective in the gut. It will be important as a portal for systemic infection (e.g., Salmonella to advance development of vaccines that are typhi) is an increasing problem. effective and economically accessible to those most at risk for infection and illness. Objectives: ß Define how common conditions such as age, The use of probiotics (ingested microbes that malnutrition, or diabetes mellitus modify can modify intestinal microbial populations in mucosal innate and adaptive immunity and a way that benefits the host) has moved from physiology, altering susceptibility to enteric concept to demonstration of unique benefits illnesses and vice versa. by specific microorganisms for a given patient ß Understand the role of host genetics in the population. However, the science of probiotics response to GI infections. is still in its infancy, and scientific claims for ß Understand the mechanisms of action of improved outcomes, such as disease prevention probiotics and prebiotics. and treatment, are often unsubstantiated. It is ß Conduct appropriately designed and powered increasingly clear that benefits from probiotics large-scale, placebo-controlled, randomized, are mostly mediated by the effect that intestinal double blind clinical trials to demonstrate safety microflora have on gut barrier function and and efficacy and substantiate the potential for host immune response. Identifying the role and novel interventions to treat or prevent enteric mechanism of action of probiotics for treatment infections. and prevention of diarrhea, reducing the risk of ß Promote strategies to reduce nosocomial enteric intestinal disease (e.g., necrotizing enterocolitis), infection, such as handwashing. and modulating host immune response to ß Investigate and promote novel strategies to extraintestinal disease, such as allergic disease, are reduce and treat C. difficile infection. important potential areas of future research. ß Develop new strategies for microbial killing or stasis, especially for infections in which there is Antibiotic-associated diarrhea and colitis were emerging antimicrobial resistance. recognized soon after antibiotics became available, ß Advance vaccine strategies for appropriate and C. difficile was identified as a causative agent pathogens to reduce morbidity and mortality of in the 1970s. In the last few years, C. difficile has enteric infection. Integrate measures to control been more frequent, more severe, more refractory enteric parasitic infections, including vaccine to standard therapy, and more likely to relapse. distribution and potential mass treatment This pattern is widely distributed in the U.S., protocols (e.g., wide-scale de-worming, Canada, and Europe and is now largely attributed preventive chemotherapy agents). to a new strain of C. difficile, designated BI/NAP1

Infections of the Gastrointestinal Tract 75 Goaloalss for for Rese Rarcesearchh

Research Goal 3.3: Understand and modulate on cognition, development, and health. the long-term intestinal and non-intestinal Comprehensive outcome measurements consequences of GI infection. should be developed to guide and standardize assessments in different populations. Diarrhea is well-recognized as a leading cause of ß Identify biomarkers to predict the development childhood mortality and morbidity in developing of systemic diseases secondary to the exposure to countries; however, possible long-term deficits enteric pathogens. from heavy diarrhea burdens in early childhood ß Attenuate host response to specific human include delayed growth and cognitive development infections. beyond the immediate impact of infection. It is ß Define the relationship between intestinal unclear whether mechanisms such as disruption of infection and chronic GI (i.e., IBS, IBD) and the mucosal barrier account for these long-term non-GI diseases. sequelae of acute infection. ß Conduct feasibility studies on developing vaccines or other agents against “non- Similarly, long-term consequences of acute infection pathogenic” bacteria that might trigger in developed countries include persistent IBS. pathologic intestinal inflammation. Infection by pathogenic organisms leads to mucosal ß Identify the consequences of reducing the damage and disruption of the gut’s extensive burden of intestinal infection and/or altering commensal microflora—factors that may lead to the microflora, such as those anticipated by the prolonged bowel dysfunction. Although many hygiene hypothesis. patients improve over the first 6 months, recovery can be slow, with approximately 50 percent still having symptoms at 5 years. Research Goal 3.4: Understand the human microflora and microbiome in health and disease Although it is clearly a goal to reduce the burden and modulate them for beneficial effects. of acute enteric infection, understanding the unintended consequences of such a strategy is Microorganisms live in complex environments critical. The hygiene hypothesis suggests that both ex vivo and in vivo. Current information increases in chronic inflammatory disorders (e.g., about synergy between enteric pathogens and allergies, IBD, and autoimmunity) in developed other organisms is limited. Many species of countries are partly attributable to diminishing bacteria regulate gene expression in response to exposure to organisms that were part of increasing cell population density; collectively, this mammalian evolutionary history. Crucial organisms, phenomenon is called quorum sensing. Quorum- including bacteria, helminths, and saprophytic sensing bacteria produce and release signaling mycobacteria, are recognized by the innate immune molecules (autoinducers) that accumulate in the system as harmless or “tolerable.” This recognition environment as cell density increases. Quorum can trigger development of regulatory dendritic sensing is used by bacteria to communicate within cells that may drive regulatory T cell responses to the same species and across species. When a simultaneously processed “forbidden” target self- threshold stimulatory concentration of autoinducer antigens of the chronic inflammatory disorders. is achieved, a signal transduction cascade is initiated that is translated into a change in behavior of the Objectives: organism. Only recently has the complexity and ß Understand the short-term (and long-term) scope of quorum sensing in bacterial regulation burden and impact of enteric infections been appreciated. Far from being isolated entities,

76 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases GOALS FOR RESEARCH

bacteria exist in multifaceted and communicating ß Develop and make accessible computational populations. The outcome of this cross-talk can lead approaches and tools to assay the microbiome to either severe or attenuated infections. in the gut in a variety of disease states. ß Determine whether the microflora is altered The human intestine contains trillions of bacteria, under pathophysiologic conditions (e.g., hundreds of species, and thousands of subspecies. infectious diarrhea, IBS, IBD, obesity) in animal Little is known about the selective pressures that have models and in people. shaped and are shaping this community’s component ß Modulate the GI microflora to prevent systemic species, which are dominated by members of the and intestinal diseases. Bacteroidetes and Firmicutes divisions. Obese mice ß Determine whether genetically modified have a different microflora than non-obese mice. In microorganisms can deliver therapeutic addition, in contrast to mice with a gut microflora, molecules to the GI tract. germ-free animals are protected against the obesity ß Define the composition of the gut microflora in that develops after consuming a Western-style, high- development, including during breast feeding, fat, sugar-rich diet. These observations underscore the formula feeding, perinatal stress, and illness importance of considering the intestinal microflora early in life. as an important participant in the metabolome in a ß Determine the role of prebiotics, probiotics, supraorganismal context and perhaps as a key driver and symbiotics in modulating the long-term of such diseases as obesity. composition of the intestinal microflora in the neonatal interval and beyond. Objectives: ß Define the role of archaea in the GI tract in ß Develop a comprehensive understanding of the health and disease. intestinal microbiome and the effect of the host genome on microbial colonization. Understand the consequences of interactions between GI pathogens and normal gut microflora for GI function.

MAJOR CHALLENGES AND STEPS challenges. The development of small TO ACHIEVE the RESEARCH GOALS models and in vitro models to study intestinal physiology, mucosal immunity, and microbial- Technologies to study intestinal infection: host interactions will provide fundamental Efforts that replace archaic enteric pathogen insights before trials in humans. New in detection technology and can identify agents vivo imaging systems that can be applied in across taxa would accelerate research on animal models and humans will enhance our intestinal infections. The development of rapid understanding of the pathogenesis of and sensitive diagnostics to detect all known infectious agents. enteric pathogens would facilitate research and improve patient care. Other technologies Therapeutic development for intestinal that could be developed include genetic and infections: Despite the effectiveness of replication tools to study viral pathogens and vaccines in eliminating a subset of infectious resources to study viral pathogens in human diseases, several challenges must be

Infections of the Gastrointestinal Tract 77 addressed to develop vaccines for enteric New databases, communication networks, and infections. Vaccines for some pathogens scientific resources are required to develop (e.g., enterotoxigenic E. coli, Shigella, and sustain longitudinal, large population Campylobacter, and Norovirus species) field studies and productive international will require multiple or yet-to-be-defined collaborations. Infrastructure and improved antigens (e.g., enteroaggregative E. coli and technology to more promptly identify infected Cryptosporidium species). Also, many oral patients would improve our understanding of vaccines are less immunogenic when given to the epidemiology of foodborne diseases. malnourished persons who might need them most; vaccines that target populations in Methods to modulate the human developing countries, such as those for cholera, microbiome: Improved understanding of typhoid, and parasites, will require incentives the intestinal microflora and microbiome to bring them to and maintain them in would enhance our potential to identify novel global markets. approaches to treatment and to identify those microbes that result in long-term GI The development of new interventions, either sequelae. Learning how to segregate the vaccines or other methods, is hampered important variables and developing adequate by insufficient knowledge of the pathways bioinformatic/computational power will be triggered by pathogens. It is possible that by required in order to make sense out of the establishing correlates of protective immunity massive data resulting from characterization for GI pathogens, we would eliminate the need of the trillions of organisms in the intestine. for challenges or field trials to study efficacy The formation of multidisciplinary teams of and, thereby, speed development of licensed researchers in human studies would enable candidate vaccines. A final challenge is that the field to obtain a complete picture that probiotics are classified as food supplements incorporates immune function, transcriptome, and/or natural health products that do not microbiology, and clinical responses. Filling require rigorous clinical evidence for efficacy; the pipeline by fostering the careers of new this situation directly conflicts with current investigators in this area is a priority. The and proposed uses of these agents as drugs to resource development and research programs treat disease. supported by the Human Microbiome Project under the auspices of the NIH Roadmap for Resources for intestinal infection Medical Research will be critical for research research: Repositories for human biologic efforts to prevent and treat human intestinal samples, research reagents, and animal models infections through microbe-based approaches. are needed to promote progress in the field.

78 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Infections of the Gastrointestinal Tract 79 Arrows point to cells within human colon cancer samples producing a protein called CD133, which served as a marker for identifying cells that initiate colon cancer. Markers such as this one may be helpful for targeting future therapeutic approaches.

Image courtesy of Dr. Ruggero De Maria. Reprinted by permission from MacMillan Publishers Ltd: Nature, 445:111-115, copyright 2008.

0 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Cancers of the Digestive System

SUMMARY OF RESEARCH GOALS

Recognizing the substantial public health impact of digestive system cancers, the Commission recommends several research goals targeted at improving the detection, prevention, and treatment of these diseases. Research is needed to develop more efficient screening tools to predict and detect digestive tract cancers and pre-malignant conditions that frequently progress to cancer. These efforts would be bolstered by identifying health disparities that influence an individual’s susceptibility to digestive system cancers or their response to treatment. Understanding the underlying mechanisms common to all digestive cancers and identifying biomarkers to detect disease or predict response to treatment would accelerate the search for safe, effective therapies. In order to develop targeted strategies for cancer detection, prevention, and treatment, it is critical that researchers identify the genetic risk factors that predispose an individual to a specific form of digestivecancer, such as esophageal cancer, pancreatic cancer, gastric cancer, colorectal cancer, or certain rare gastrointestinal (GI) cancers.

Together, these research goals aim to improve the health and lives of people at risk for or living with digestive cancers.

Cancers of the Digestive System 81 introduction and Background In the early 1900s, cancer of the distal stomach was the leading cause of death from cancer The digestive system, including the gut, in the U.S. Seventy years later, gastric cancer pancreas, liver, and biliary tree, is the site of prevalence has declined to represent the 13th more cancers and the source of more cancer leading cause of death from cancer in the mortality than any other organ system in the U.S., but it is still ranked second worldwide. body. More than 270,000 Americans develop Improvements in food storage and public a cancer of the GI tract each year, and half of sanitation are considered the major reasons these patients will die from the cancers for the decline in these statistics, suggesting (Table 2). that this disease can be prevented. In 1994, the World Health Organization designated The burden of digestive cancers on the Helicobacter pylori as a definite carcinogen, American population is considerable in based on the epidemiologic evidence linking terms of numbers of new cases, deaths, and the chronic gastric inflammation induced by economic costs for diagnosis and treatment. H. pylori to cellular transformation in Research directed at understanding the causes the stomach. of the digestive cancers will help reduce their incidence, prevent deaths, and lower Esophageal cancers represent an enormous healthcare costs. burden of morbidity and mortality worldwide. In 2002, there were an estimated 462,117 new Of the digestive cancers, colorectal cancer is cases and 385,892 deaths from esophageal the most prevalent, with a lifetime risk in the cancer worldwide, making it the eighth and U.S. of 5-6 percent. Colorectal cancer is unique sixth leading causes of cancer and cancer among cancers because it is highly amenable mortality, respectively. Developing strategies to screening programs that can reduce to reduce the mortality of esophageal cancer cancer mortality by early detection and, more is complicated by the fact that the two major importantly, reduce the incidence of invasive histologic subtypes (squamous cell cancer by removing pre-malignant lesions. and adenocarcinoma) show marked regional Colorectal cancer incidence and mortality have variation in incidence, differ substantially been falling over the past 2 decades for reasons in etiology, and arise in different tissues. that are not fully explained. High mortality is one of the main shared characteristics of the two histologic subtypes.

Table 2. Incidence and Mortality of GI Cancers in the U.S. (2008 estimated)

Overall Male Female Annual # of Deaths Cancer Site Incidence Incidence Incidence Deaths Divided by Incidence (%) Esophagus 16,470 12,970 3,500 14,280 87% Stomach 21,500 13,190 8,310 10,880 51% Small intestine 6,110 3,200 2,910 1,110 18% Pancreas 37,680 18,770 18,910 34,290 91% Liver and intrahepatic duct 21,370 15,190 6,180 18,410 86% Gallbladder and biliary ducts 9,520 4,500 5,020 3,340 35% Colon and rectum 148,810 77,250 71,560 49,960 34% Anus and anorectum 5,070 2,020 3,050 680 13% Other digestive organs 4,760 1,470 3,290 2,180 46% TOTALS ,0 ,0 ,0 ,0 0%

82 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Esophageal have been Research on digestive cancers has been generally reported to be increasing in incidence in directed toward understanding the basic biologic many regions of the Western world. Although mechanisms of tumors. Despite major advances esophageal cancers are less common than in this area, the research community is far from lung, breast, , and colon cancers in understanding how digestive cancers form, the U.S., they are nevertheless the seventh grow, and spread. An improved understanding leading cause of cancer death among U.S. is crucial to lowering the incidence of digestive males. Between 1972 and 2002, the incidence cancers in the diverse U.S. population, identi- of esophageal adenocarcinoma in Caucasian fying predictive biomarkers to prevent cancer males increased more than 600 percent, occurrence or recurrence, and developing novel making it the most rapidly increasing cancer and creative approaches toward prevention or in the U.S., as well as in many other regions of treatment strategies. the Western world. This chapter addresses digestive cancers, Pancreatic cancer is the fourth most common except liver cancer (see the chapter on Diseases cause of cancer death in the U.S., with an of the Liver and Biliary System), with a focus annual incidence of 11.4 per 100,000 men on the four most common digestive cancers: and women. Based on rates from 2002 to colorectal, esophageal, gastric, and pancreatic. 2004, 1.31 percent of men and women (1 in Rarer GI cancers (e.g., cancers affecting the 76) born today may be diagnosed with cancer small intestine, anus, gastrointestinal stromal of the pancreas at some time during their tumors (GIST), gastrointestinal , lifetime. Ninety-five percent or more of the and ) are discussed in aggregate. The deaths from pancreatic malignancy are due chapter outlines a set of research goals that to ductal , the most common and should improve our overall understanding of highly metastatic form. Less common tumor basic mechanisms that are relevant to cancer types can occur in the pancreas, but are often etiology and prevention, as well as specific goals less lethal or even benign. The less frequent that are directed at individual cancer types. mesenchymal, hematopoietic, and endocrine tumors often share greater similarity with tumors occurring in other organs than with rEcEnt rESEarcH advancES the pancreas-specific tumors. Pancreatic cancer is usually not diagnosed until after the Genetic instability as an underlying disease has been manifested through clinical mechanism of cancer symptoms; as a result, only 20 percent are considered appropriate for surgical resection A fundamental principle underlying the of the original tumor at the time of diagnosis. formation of digestive cancers is the sequential Even those patients whose cancer is deemed acquisition of alterations in specific genes. surgically resectable usually have local These alterations lead to genetic instability node spread at the time of surgery, and nearly that fuels the growth of cancer cells. A fraction all have micro-metastatic disease that is of cancers exhibits a form of genetic instability simply undetected at presentation. The overall called microsatellite instability, which is often 5-year survival rate for pancreatic ductal characterized by DNA mismatch repair (MMR) cancer is less than 5 percent. deficiency. Loss of MMR functions renders tumor cells susceptible to the acquisition

Cancers of the Digestive System 83 of somatic mutations throughout the genome. stem cells, a property known as self-renewal, A more common form of genetic instability and they can produce cells that differentiate. is chromosomal instability, which is usually Recent studies support the concept that cells manifested by aneuploidy (a change in the with properties of stem cells are integral to number of chromosomes). For example, multiple the development and perpetuation of human studies have established that esophageal digestive cancers. Eradication of the stem adenocarcinoma develops in association with cell component of a tumor may be essential chromosomal instability, which generates to achieve stable, long-term remission or cure non-random loss of heterozygosity involving of cancer. Advances in the knowledge of the chromosomes 9p, 17p, 5q, and 18q, as well as properties of stem cells have made the specific tetraploidy (another form of altered chromosomal targeting and eradication of cancer stem cells a number) and aneuploidy. Additionally, telomere topic of considerable interest. The concept that dysfunction has been shown to contribute to the GI cancers arise from hematopoietic precursor onset of genetic instability in somatic cells. cells is a theme that was initially shown in the liver. The identification of - Epigenetic silencing of gene expression as derived cancer stem cells in gastric cancer is a mechanism in cancer formation the first evidence that a luminal organ may show this property. Chromosomal alterations or modifications have been associated with all stages of digestive Cellular receptors and related signaling tumor formation and progression. The best- pathways as targets for cancer therapy characterized form of chromosomal alteration is epigenetic silencing by hypermethylation Hormones, cytokines, and growth factors of the promoter regions of genes that have control many aspects of cell proliferation, important regulatory functions in cell growth differentiation, migration, angiogenesis, or checkpoint maintenance. Epigenetic apoptosis, and senescence. These chemical silencing can occur during the early stages signals are propagated from the cell surface of tumor development, thus inducing the to intracellular processes via sequential aberrant, early clonal expansion due to kinase signaling, arranged in modules that alterations in the various regulatory steps exhibit redundancy and cross-talk. This signal affected by genetic silencing. Recent studies transduction system comprising growth have also suggested the presence of a unique factors, transmembrane receptor proteins, type of cancer exhibiting the CpG island and cytoplasmic second messengers is often methylator phenotype (CIMP). CIMP tumors exploited to optimize tumor growth and represent a clinically and etiologically distinct metastasis in malignancies. Thus, receptors group of cancers that is characterized by and their signal transduction systems “epigenetic instability.” Lastly, a form of represent an attractive target for digestive chromosomal modification called loss of cancer therapy, and several new drugs have imprinting of specific genes involved in growth been developed and shown to be effective. regulation has been shown to predispose to cancer formation. Cancer genomics and proteomics

Cancer stem cells Advances in genomics, proteomics, and molecular pathology have improved the Stem cells are characterized by their ability to ways by which human cancers are detected, divide asymmetrically—they can make more classified, staged, monitored, and treated. The

84 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases identification of genetic alterations in cancers Mouse models that emulate human gene in unprecedented detail has accelerated function in cancer the understanding of the genetic basis of human cancers and provided new targets for Mouse models with deleted gene function or diagnostic and therapeutic interventions. targeted similar to observed human mutations demonstrate some recapitulation of Improvements in approaches and devices human colon cancer and include alterations of that detect and treat esophageal cancer in the APC gene, TGF-β signaling pathway, and high-risk patients the PTEN gene. New animal models of gastric cancer have uncovered a number of genetic Endoscopic imaging of squamous esophageal targets that may be critical for gastric cancer cancer using Lugol’s solution has improved formation including the cytokine receptor detection of this cancer in high-risk patients. subunit gp130, Runx3, trefoil factor TFF1, Narrow band imaging and improved endoscopic and STAT3. New animal models of pancreatic magnification has enhanced the ability of the cancer recapitulate some of the genetic and endoscope to assess areas of neoplasia without ductal abnormalities known to exist in human requiring topically administered contrast pancreatic cancer, including the generation of agents. Mucosal resection devices have been invasive ductal cancers. These highly relevant developed that permit single or multiple animal models may aid in the understanding resections of the mucosa to allow removal of mechanisms for cancer formation and may of large portions of tissue for therapy and accelerate the preclinical development and diagnosis and precise determination of the evaluation of new therapeutic compounds. depth of invasion. Mucosal ablation devices (e.g., photodynamic therapy, thermoablation, Inherited risk factors and genetic radiofrequency ablation, cryotherapy) have signatures for pancreatic ductal cancer been created specifically for theesophagus to ablate pre-malignant cells and, in some cases, Researchers have advanced our understanding malignant cells. of the degree of risk acquired by members of affected families, genetic locations linked to Genetic risk for gastric and risk (such as 4q32-34), and investigation of cancer candidate genes that may be responsible for pancreatic ductal cancer. Special pancreatic Researchers have identified polymorphisms tissue abnormalities have been found in in cytokine genes that predispose individuals these families, and a screening program that to gastric atrophy and cancer. This discovery includes endoscopic ultrasound (EUS) has underscores two important principles in improved the detection of early and curable gastric cancer development: that the host pancreatic lesions. In nearly 20 percent of response (i.e., inflammation) to bacteria families most affected by ductal cancer, the (presumably H. pylori) is essential to cancer causative gene is now known. Approaches to pathogenesis; and that atrophy serves as an treatment of ductal pancreatic cancer have indicator that the mucosa is developing pre- taken advantage of genetic signatures of the neoplastic changes. cancer cells to test responsiveness to specific and available drugs. For example, mutations

Cancers of the Digestive System 85 in the BRCA2 gene and cellular pathway cancer centers, effective reduction in the are being used investigationally to assign morbidity and mortality of the disease, optimal individual patients to treatment with specific pre-surgical screening to diagnose the tumors families of drugs or to explain the different by and biopsy, improved planning responses of patients to such drugs. Also, of the surgical approach for tumors that are compounds targeting cell-surface growth factor anatomically difficult to remove, and better receptors are being evaluated in clinical trials means to combine surgery with radiation and based on studies showing abnormal expression chemotherapy to improve the quality and of such targets in the ductal cancers. duration of life after ductal cancer surgery.

Imaging techniques for the detection Improvements in colorectal cancer screening and staging of pancreatic cancer and GI luminal cancers Colorectal cancer is one of a small number of human cancers for which screening of the Advances in the quality of high-resolution general population is cost-effective and can CT and MRI scanners and EUS have led to significantly improve outcome. a marked increase in the detection of small permits both the detection of early cancers pancreatic cystic tumors and solid masses. and the removal of precursor lesions, which EUS allows tumor features to be evaluated has the potential to reduce morbidity and using complementary imaging technologies mortality due to colorectal cancer. Technical and to be directly sampled by fine-needle advances that include CT colonography aspiration. Laboratory evaluation of the fluid (), fecal DNA testing for for tumor markers (e.g., carcinoembryonic colorectal cancer, and fecal immunochemical antigen), cytological evaluation of aspirated tests provide an opportunity to improve cells, and molecular analysis of suspicious cells digestive health. for specific gene mutations and markers of aneuploidy represent significant advances in Advances in genetic diagnosis of the early detection and diagnosis of pancreatic colorectal cancer cancers and precancerous lesions. EUS, , double balloon , Colorectal cancer has an important familial and improvements in the optics of endoscopes component. Approximately one third of are improving detection of GI luminal cancers. colorectal cancer patients have a first- or second-degree relative with colorectal cancer. Immunologic and surgical approaches to Approximately 4 percent of all colorectal pancreatic cancer therapy cancer patients have well-defined syndromic forms of colorectal cancers. Advances in Efforts are underway to: develop antibody understanding the genetic risk factors for therapy against specific growth factor colorectal cancer include improved tests for receptors; develop and conduct clinical trials alterations in the DNA mismatch repair of a post-surgically administered cancer cell genes (MMR) that cause Lynch syndrome (or vaccine that generates immune responses HNPCC); the discovery of a recessive form against tumor-specific proteins; and develop of familial polyposis, called MYH-associated new immunologic agents designed to elicit polyposis; and the elucidation of “Syndrome X,” more direct immune responses against the which represents familial clusters of colorectal same tumor markers. Advances in the surgical cancer that are not attributable to an inherited treatment of pancreatic cancer include the mutation of a known DNA MMR gene. establishment of highly experienced pancreas

86 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Chemoprevention and nutriprevention of Targeted treatment for gastrointestinal colorectal cancer stromal tumors (GISTs)

Beginning in 1980, it was recognized that GISTs are tumors arising in the certain non-steroidal anti-inflammatory drugs of the GI tract due to constitutively activating (NSAIDs; beginning with sulindac) could mutations in either the PDGFRA or KIT induce the regression of in patients receptors on the interstitial cells of Cajal. with familial adenomatous polyposis (FAP). Specific molecular therapies targeting the Subsequently, it was shown that selective tyrosine kinase domain of PDGFRA and KIT, Cox-2 inhibition can significantly reduce the which were initially developed to treat certain numbers of adenomas and carcinomas in types of leukemia, have proven to be clinically patients who have had colorectal neoplasms in useful and superior to chemotherapy and the past. However, many of these agents have surgery for the treatment of GISTs, although unacceptable toxicities. The development of they are not curative. safer anti-neoplastic drugs that inhibit Cox-2 could improve treatment outcomes.

GOALS FOR RESEARCH 10

The digestive cancers represent a diverse group of Strategies to effectively screen and prevent digestive disorders with respect to etiology, prevention, and cancers could prove very cost-effective for society. treatment. The goals for research that follow include ones that are broadly applicable to digestive cancers, Objectives: as well as specific goals for individual types ofcancer. ß Understand the major risk factors for digestive cancers. ß Develop risk modeling and stratification to identify Research Goal 4.1: Develop population- high-risk populations for digestive cancers. based strategies for screening and prevention of ß Conduct large-scale trials of screening modalities digestive cancers. to determine efficacy and cost-effectiveness and integrate effective strategies into practice. For some digestive cancers, such as colon cancer, ß Improve imaging modalities to detect and/or technologies are available to detect pre-malignant remove pre-malignant or early malignant digestive lesions that might be used for population-based cancers when they are more likely to be curable. screening. Other technologies can remove these lesions, reducing the cancer risk for the patient. Clear and cost-effective utilization of the technologies Research Goal 4.2: Ascertain the importance, will need to be evaluated. Other digestive cancer detection, and natural history of pre-malignant prevention strategies might target high-risk conditions progressing to digestive cancer. populations, such as those with family histories of cancer, GI inflammatory diseases, high-risk Studies to address the natural history of pre- behaviors, or the presence of certain biomarkers. malignant lesions that predispose to digestive

10 Research Goals are numbered for ease of reference only; the numbers do not indicate prioritization of scientific topics.

Cancers of the Digestive System 87 Goaloalss for for Rese Rarcesearchh

cancers are crucial. Adenomatous polyps— ß Define the mechanisms that predispose patients detectable precursors to colorectal cancer—have with IBD for digestive cancers. been extensively studied. The importance of small ß Determine the role of the microflora in the adenomas is unknown, yet critical in evaluating the initiation or propagation of digestive cancers. value of CT colonography. Rates and mechanisms for benign to malignant transformation of esophageal, gastric, and pancreatic lesions are likewise not Research Goal 4.3: Evaluate health disparities known. The accumulation of genetic derangements in digestive cancer etiology, risk, treatment required to develop the cancer and its ability to management, and outcomes. metastasize needs to be better understood. We also need to learn how , pancreatic The U.S. population is extremely diverse, and intraepithelial neoplasia, or other precursor lesions some racial and ethnic groups have higher risks for develop from interaction with factors in the local developing digestive cancers. One factor may be environment. Indeed, environmental factors that single nucleotide polymorphisms (SNPs) of disease- are responsible for genetic derangements are largely modifying genes, but other genetic and epigenetic unknown for any of the digestive cancers. Portions factors may influence race-related cancer risk. Some of the GI tract have the most diverse environmental- groups treated for digestive cancers do not have host interactions in the entire body, with food and the same response rates to therapies or the same waste , along with the high concentration detection rates for pre-malignant or malignant of microbes, present intraluminally. Commensal conditions. Furthermore, end-of-life care varies bacteria, as well as viral, bacterial, parasitic, and among the groups for unknown reasons. Research to other infections, may directly influencecancer risk explore these racial and ethnic differences provides by affecting the underlying genetics of digestive an opportunity to eliminate disparities in digestive system cells. Inflammatory bowel diseases IBD),( cancer prevention, detection, and treatment. which result from a disturbed host-environmental interaction in the gut, are associated with a marked Objectives: increased risk for cancer development that is not ß Conduct clinical studies on access, utilization, completely understood. In addition, numerous treatment, and outcomes of patients with syndromes can lead to the development of digestive digestive cancers who belong to diverse ethnic, cancers, such as FAP, Gardner’s syndrome, Lynch racial, or high-risk groups. syndrome, and diseases like gastroesophageal reflux ß Understand the influence of genetic factors on disease and hepatitis. cancer risk, prognosis, and response to therapy. ß Investigate the influence of gender oncancer Objectives: risk, prognosis, and outcomes of patients with ß Characterize the genetic defects and clinical digestive tract cancers. behaviors associated with syndromes that predispose to digestive cancers. ß Develop and study preclinical in vitro and in vivo Research Goal 4.4: Improve outcomes in the models of digestive cancers to recapitulate the care of digestive tract cancer patients. natural history seen in humans. ß Determine the natural history of pre-malignant Patients who develop digestive tract cancers are lesions in the development of digestive cancers. faced with surgery, chemotherapy, and radiation ß Define the role ofinflammation in digestive therapy, and may experience behavioral and social cancer development. changes after their diagnosis. Improvements in

88 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Goals for Research

medical treatment may prolong life. Creative ß Utilize preclinical in vitro and in vivo models of support systems and educational mechanisms digestive cancers to ascertain biomarkers that may improve a patient’s mental outlook and predict tumor behavior and response to therapy. the management of their cancer. of chemotherapy and/or radiation are common. Therapies to counteract the side effects are not Research Goal 4.6: Evaluate nutriceutical, necessarily effective and can adversely influence probiotic, chemopreventive, and targeted therapies palliation or potential cure. Completion of therapy in digestive cancers. is a goal to offer the best chance for those who are attempting cure or remission. All digestive cancers are associated with certain risk factors, and all cancers have accumulated genetic Objectives: and epigenetic derangements that are favorable ß Conduct studies to determine the optimal for the cancer and its cells to proliferate. Natural or chemotherapy and/or —before target-developed compounds may be associated or after surgery—for best long-term survival with reduced risk of developing a cancer, and such based on stage, biomarkers, or genetic make-up compounds might be effective in combating the of the patient or patient’s tumor. disease once developed. ß Determine mechanisms for tumor resistance to therapy and develop strategies to overcome Objectives: resistance. ß Utilize preclinical in vitro and in vivo models ß Develop approaches to minimize the side effects of digestive cancers to ascertain potential of chemotherapy and/or radiation therapy. effectiveness and mechanisms of preventive ß Investigate strategies to improve behaviors for agents and small molecules. optimized cancer treatment, including self- ß Conduct large-scale, randomized clinical trials management or other modalities. utilizing agents or targeted therapies to determine effectiveness in prevention or treatment of digestive cancers. Research Goal 4.5: Develop biomarkers to detect neoplasia, target therapy, and evaluate therapeutic response in digestive cancers. Research Goal 4.7: Understand the molecular and cellular mechanisms common to all Biomarkers could be used to detect the possible digestive cancers. presence of a disease and to select the higher risk population for screening. Additionally, biomarkers Many features of cancer must be understood could track or predict the occurrence or recurrence broadly—how it develops, what subpopulations it of a digestive cancer or pre-malignant condition. affects, and what features distinguish the cancer. Utilization of an ideal biomarker for each of the This information gives researchers opportunities digestive cancers would greatly reduce costs to to track the disease precisely and to determine society and improve the ability to target high-risk if an intervention is effective for society or individuals for diagnosis and intervention. individually for the patient. Common themes from the understanding of one digestive cancer may Objectives: be utilized to study other digestive cancers. For ß Develop improved population-based example, the basic finding ofgenomic instability is a assessment of risk for digestive cancers that can key factor underpinning multiple cancers. Likewise, be detected in blood. inflammation is a common condition that precedes

Cancers of the Digestive System 89 Goaloalss for for Rese Rarcesearchh

many digestive cancers. Tumor growth is influenced Objectives: by the local microenvironment that helps sustain and ß Perform comprehensive genetic analyses of propagate cancer cells. esophageal and adenocarcinoma. Objectives ß Develop non- or minimally invasive imaging ß Define genetic and epigenetic mechanisms that and/or molecular techniques to detect pre- characterize digestive cancers. malignant changes in the esophagus. ß Characterize digestive cancer stem cells and ß Discover biomarkers for prediction and factors in the local tumor microenvironment niche evaluation of therapeutic response in that support and propagate the cancer. . ß Ascertain molecular signatures and the presence ß Determine the factors that lead to trans- of commensal microflora for evaluation of linkage formation of normal esophagus to Barrett’s with population-based risk for digestive cancers. epithelium and those that lead to further ß Determine the role of infection or host integration progression to adenocarcinoma, including the of microbes in risk for digestive cancers. potential role of stem cells in the process. ß Evaluate the role of upper endoscopy and other technologies for screening and surveillance of Research Goal 4.8: Determine the risk factors Barrett’s esophagus. and pathogenesis of squamous carcinoma and ß Evaluate new techniques to ablate Barrett’s adenocarcinoma of the esophagus and devise new epithelium, dysplasia, or early carcinoma to methods for detection, diagnosis, treatment, and prevent death due to adenocarcinoma. prevention of these diseases.

From 1979 to 2004, esophageal cancer, particularly Research Goal 4.9: Understand the molecular adenocarcinoma, became one of the most rapidly profiles of various types ofgastric cancer to improve increasing cancers in the U.S. Currently, the risk stratification, prevention, and treatment. majority of afflicted persons die as the disease commonly progresses undetected until symptoms Gastric cancer is not one disease. Cancers that occur. Moreover, mortality from esophageal develop in different regions of the stomach (e.g., adenocarcinoma has not significantly decreased antrum, corpus, fundus, cardia) are likely to have over the past decade. To address this issue, it different risk factors and different biologic behavior. will be important to understand how the normal Being able to distinguish the different types of esophageal lining changes to the pre-malignant tumors is a critical and necessary step for making lesion of Barrett’s esophagus and, ultimately, progress in this field. By understanding the basic into esophageal adenocarcinoma. Factors that biology of the various types of gastric cancer, influence this transformative process, such as acid innovative strategies for prevention and therapy can exposure, tobacco use, and obesity and other local begin to be developed. environmental influences on the one hand and stem cell genetic changes and chemopreventive Objectives: interventions on the other hand, will be key to ß Ascertain a complete molecular profiling of the understanding and affecting disease pathogenesis. histological types of gastric cancers from different locations within the stomach.

90 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Goals for Research

ß Develop a molecular roadmap for gastric cancer ß Improve imaging technologies for early development that mirrors the known phenotypes. detection of pancreatic cancer. ß Develop better tools to conduct transgenic animal ß Devise novel molecular therapeutics based on studies to further our understanding of gastric understanding of pathogenesis. mucosal biology. ß Provide infrastructure to accelerate research ß Refinerisk stratification for screening and by developing biosample, imaging, and data surveillance of gastric cancers. repositories.

Research Goal 4.10: Define the genetic and Research Goal 4.11: Identify genetic and environmental factors contributing to pancreatic environmental risk factors for colon cancer and cancer and its precursor lesions and devise new devise improved approaches for screening, early methods for early detection, treatment, and diagnosis, treatment, and prevention of colon cancer. prevention. (See also Goal 1.3.)

Pancreatic , or pancreatic cancer, Because of its major impact on public health and has a 5-year survival rate of less than 5 percent. the opportunities to further reduce the incidence By the time patients have symptoms, less than 20 and mortality of this disease, the focus on colorectal percent are deemed to be surgical candidates for cancer should be expanded. Areas of colorectal attempted cure. Pancreatic cancer can develop in cancer research that are particularly important the setting of chronic inflammation and in familial include primary prevention (e.g., novel dietary pancreatic cancer syndromes and, in this small approaches and viral vaccines), discovery of but important subset of patients, precursor lesions genes that produce hereditary colorectal cancer such as pancreatic intraepithelial neoplasms might syndromes, understanding the natural history of be identified that conferrisk for progression to pre-malignant colorectal lesions, and integrating cancer. Differentiating benign from malignant early genomics research with the clinical application of lesions by imaging or biomarkers will be central to individualized medicine. Because colorectal cancer determining optimal patient candidates for surgical screening has been demonstrated to decrease cure, which would minimize the use of surgery in incidence and mortality, efforts should be made those who may not require this intervention and to expand the use of screening, to understand the direct better utilization of chemoradiation therapy. natural history, and to stratify patients by risk status. Small colon polyps have an enormous impact on Objectives: clinical practice, even though the likelihood of ß Define the geneticrisk factors for pancreatic malignancy is small, as most patients undergoing cancer in both familial cases and sporadic disease. colon surveillance have only small polyps. ß Define environmentalrisk factors that contribute to pancreatic cancer. Objectives: ß Define early ductal precursor lesions and factors ß Evaluate chemopreventive and other primary that contribute to progression to cancer. prevention strategies against colorectal cancer. ß Identify markers for early lesions and risk for ß Improve means to identify patients, characteristics progression to cancer. of the colon, or pre-malignant lesions that give rise to the greatest risk for colorectal cancer.

Cancers of the Digestive System 91 GOALS FOR RESEARCH

ß Determine strategies to expand the use of cancers occur less often than the organ-based colorectal cancer screening in clinical practice. cancers, but many of these occur with higher ß Determine the natural history of small colorectal frequency in certain populations. For example, adenomatous polyps, including factors and immunocompromised patients have a higher markers for malignant progression and potential prevalence of lymphomas; those with celiac role of chemoprevention. disease have a higher prevalence of small intestinal ß Determine the potential role of proximal lymphomas; and anal cancers are linked to hyperplastic polyps and serrated adenomas in infection with human virus. Collectively, progression to colorectal cancer. this group of tumors affects approximately 15,000 ß Understand and develop models for flat adenomas Americans annually. Because of their relatively rare (i.e., non-polypoid colorectal neoplasia). occurrence, research into these conditions lags ß Continue to develop new endoscopic, imaging, behind that for organ-based digestive cancers. and other technologies for colorectal cancer screening. Objectives: ß Improve imaging technologies and therapeutic options to detect and remove small intestinal Research Goal 4.12: Understand the etiology, cancers. natural history, prevention, and management of ß Determine predictive factors or biomarkers that rare GI cancers. (See also Goal 8.4.) more accurately predict patient outcome, such as with MALT and H. pylori eradication; The rarer GI tumors include cancers affecting the anal carcinoma and or human small intestine and anus, GISTs, gastrointestinal papilloma virus infection; or the development and lymphomas, and carcinoids. Individually, these behavior of intra-abdominal desmoids in FAP.

MAJOR CHALLENGES AND STEPS TO cannot be performed effectively in individual ACHIEVE THE Research GOALS clinical sites with limited patient populations. The development of high-throughput genomic Collaborative research and centralized and proteomic facilities to complement the resources: Research on digestive system current Cancer Genome Anatomy Project cancers would be accelerated by promoting to profile digestive tract cancers and their mechanisms for collaborative research. For subtypes would also strengthen the entire field example, centers could be established to and promote progress. Finally, the creation collect and maintain clinical information of high-throughput drug discovery programs and epidemiologic data linked to a repository based on targeted approaches to cancer biology of biologic specimens and other data, such would present an opportunity for collaboration as gene expression profiles, SNPs, and with industry in the area of drug development other patient characteristics. Such multi- and evaluation. institutional repositories of samples and data from well-characterized patients would enable Technology development: The development collaborative research on disparities among of advanced non- or minimally invasive imaging ethnic, racial, or high-risk groups that often or molecular techniques for detection of pre-

92 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases malignant changes in digestive tract cancers Animal models: New transgenic animal has the potential to improve cancer diagnosis in models do not faithfully replicate sporadic the early stages of the disease and dramatically digestive cancer occurring in the adult human. reduce the burden of these diseases on Therefore, improved, rigorously validated individuals and the healthcare system. animal models are needed.

Cancers of the Digestive System 93 Diagram showing new genes and biological pathways associated in recent years with Crohn’s disease. New approaches, such as genome-wide association studies, have identified previously unknown genetic factors and processes that influence the development of this disease, which can inform the design of future treatment strategies.

Image courtesy of Dr. Christopher Mathew. Reprinted by permission from MacMillan Publishers Ltd: Nature Reviews Genetics, 9:9-14, copyright 2008.

 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Inflammatory Bowel Diseases

SUMMARY OF RESEARCH GOALS

Inflammatory bowel diseases (IBD) are a diverse group of digestive tract disorders of often unknown origin and complex disease management. Given the potentially severe impact of these diseases on patients’ quality of life, cancer risk, growth and development in childhood and adolescence, and other serious health issues, the Commission proposes a set of research goals that are intended to accelerate progress on understanding, preventing, and effectively managing these diseases in all patients. An urgent research goal is the development of objective criteria for IBD diagnosis and risk evaluation, based on phenotypic and genetic characteristics, which would enable reliable subclassification of patients and their diverse constellations of symptoms. Such validated criteria could facilitate clinical evaluation and disease management approaches that are tailored to individual needs and that improve the efficiency of clinical trials to test new therapies. Strategies to prevent or control IBD that could be tested include modulation of the intestinal microflora or themucosal immune system. These and other therapeutic approaches are targeted at maintaining the health of the intestinal mucosa and stimulating regeneration and repair in patients with IBD. In addition, finding ways to alleviate the unique developmental challenges faced by children with IBD is a particularly important goal in this research area.

Inflammatory Bowel Diseases 95 INTRODUCTION AND BACKGROUND the superficialinflammation found inUC. CD may affect any site within the GI tract from Inflammatory bowel diseases comprise a set mouth to rectum, though certain site-specific of chronic inflammatory disorders that affect patterns are more common. The terminal different sites within the gastrointestinal (GI) is most frequently affected, either alone tract and are not definitively attributable or in conjunction with some segment of the to any one known etiologic agent or specific colon. Similarly, one or more segments of the precipitant. Two major forms of IBD— colon may be affected independent of the designated (UC) and Crohn’s terminal ileum or more proximal areas of the disease (CD)—have been empirically defined digestive tract. In contrast to UC in which the through decades of clinical experience on the inflammatory process is typically diffuse and basis of characteristic clinical, pathologic, continuous in extent, inflammation may be endoscopic, and radiologic features. patchy and segmental in CD. Symptoms can Occasionally, overlap in some features can reflect theinflammation itself or the scarring prevent a firm diagnosis in a small proportion that can result (fibrostenotic disease). Often the of patients, who are accordingly said to GI tract becomes obstructed at the affected site. be affected by indeterminate colitis. Still In many patients, the transmural inflammation other patients are affected by a seemingly can result in pathologic connections between the distinct constellation of chronic idiopathic intestine and a variety of structures, including inflammation designated other parts of the GI tract, the bladder, the (alternatively referred to by its two variants— , and the (most commonly in the and ) in perineal or perianal region). Many times, these which the inflammatory process is milder and connections are associated with the formation manifests primarily as watery diarrhea. of abscesses. While CD can result in a wide range of symptoms, patients often experience UC is characterized by diffuse inflammation the combination of abdominal pain, diarrhea, affecting the mucosal and submucosal layers and weight loss. In pediatric patients, lack of of the colon closest to the luminal surface that growth is a particularly common manifestation. typically is most intense in the rectum and In addition to symptoms related directly to can extend proximally to varying degrees. GI tract function, a significant minority of In about a third of patients, the entire large patients with either UC or CD also experience bowel is affected. The inflammation eventuates extraintestinal manifestations due to associated in mucosal ulceration that contributes to the inflammation affecting the skin, eyes, , cardinal symptom of bloody diarrhea. While liver, and bile ducts. Although specific episodes episodes of inflammatory activity can respond or complications of CD can respond to available to therapeutic agents, additional “flares” drugs or surgical intervention, none are follow with variable frequency. The chronic curative, and disease is lifelong. inflammation increases the risk of colon cancer, making surveillance for dysplasia (a It is estimated that more than one million form of pre-cancer) necessary even if the actual Americans are affected by IBD, with similar inflammatory disease remains in remission. numbers for UC and CD. Prevalence is greater among some groups, including those of CD is more varied in its inflammatory Ashkenazi Jewish ancestry, but the diseases process and clinical manifestations. Typically, are found in all ethnic and racial groups. The inflammation affects all layers (referred to as onset of IBD is most common in the second and “transmural inflammation”), in contrast to third decades of life, though it can begin at any

96 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases time from infancy to the eighth decade. With serious side effects, including bone marrow onset in early adulthood, these disorders cause suppression, pancreatitis, and liver toxicity. many decades of pain and suffering and result More recently, antibodies that target tumor in significant lost productivity, in addition to necrosis factor (TNF), a key cytokine, have the direct costs of medical and surgical care. helped many patients who have not responded adequately to other agents. However, in addition Research suggests that increases to occasional side effects, the duration of efficacy the risk of CD, but reduces the likelihood of may be limited, and a significant number of UC. early in life also appears patients fail to respond. Surgical intervention to reduce the lifetime risk of UC, although plays a key role in the management of some the reason remains obscure. Family history patients. UC patients with severe disease that appears to be the most significant risk factor. fails to respond to medical treatment can be First degree relatives have a five- to 20-fold “cured” by total removal of the colon, most greater likelihood of developing IBD compared commonly with the creation of a neo-rectum to those from unaffected families. In absolute (pouch) using the terminal ileum. Surgery in terms, approximately 5 percent of children of CD patients is usually employed to manage a a parent with IBD will develop the disease. specific complication of the disease, typically The concordance of CD in identical twin pairs involving drainage of infection and resection may be as high as 50 percent compared to 5-10 of an affected area. However, even when all percent in non-identical twins, underscoring segments apparently affected are removed, the key role that genetic inheritance plays in recurrence of CD over time is nearly inevitable. disease susceptibility. Unfortunately, despite extensive efforts, no effective preventive interventions have been Although a variety of medications are identified forIBD. available that can control inflammation and ameliorate the resulting symptoms, none provide fully effective treatment, and almost RECENT RESEARCH ADVANCES all are associated with the risk of serious side effects. A variety of formulations that deliver IBD genetic susceptibility factors 5-aminosalicylic acid (5-ASA) can be useful in treatment of mild UC and CD and may Substantial progress has been made in also diminish the frequency and severity of identifying factors that collectively appear recurrence in UC. Select patient groups may to underlie the major forms of IBD. Research respond to use of a broad spectrum antibiotic. provides compelling evidence that individual Patients with more severe inflammation risk for developing IBD depends on the often require corticosteroids, potent anti- inherited forms of several different genes. inflammatory agents that also carryrisk of These genes control a variety of mucosal potentially severe complications, including functions, particularly those involved in suppression of normal immune defenses, regulating the interaction with and response osteoporosis, hypertension, diabetes, and others. to luminal microflora. However, genetic Agents that modulate the immune system, inheritance alone is insufficient to lead to IBD, such as azathioprine, 6-mercaptopurine, and and actual disease depends on environmental methotrexate, are often used to minimize factors, likely including the composition of the corticosteroid requirements and effect longer luminal microflora. term control, but themselves can also cause

Inflammatory Bowel Diseases 97 Mucosal barrier function and its innocuous in most people, is an essential functional alteration in IBD driver of chronic intestinal inflammation in susceptible individuals. Thus, development of Researchers have gained a more chronic colitis in murine models requires the comprehensive—but still incomplete— presence of a seemingly normal microflora. understanding of the molecular basis of Characterization of the complexity of normal barrier function. Its importance in maintaining microflora remains substantially incomplete, normal mucosal homeostasis and its disruption though some studies have suggested that in the pathogenesis of chronic inflammatory at least one class within the microflora— bowel disease have been demonstrated. designated AIEC (adherent invasive E. coli)— These advances include the composition may be more common in CD. of the tight junction and its functional regulation. Ultimately, understanding this The central role of the epithelium and dynamic regulation should enable strategies dynamic interaction between epithelium and luminal bacteria for enhancing the barrier to prevent IBD or restore it once damage has occurred. A variety of direct and circumstantial observations implicate a role for alterations of Key genes conferring risk for IBD the epithelial cell compartment in the central pathogenesis of IBD. These include development Initial genomic screening led to the of colitis in murine models resulting from identification within the IBD1 region of genetic alterations of epithelial cell-expressed NOD2/CARD15, a gene conferring risk for products and expression of proteins encoded ileal Crohn’s disease in many populations. by human IBD susceptibility genes in the More large-scale genome-wide scans using epithelium. In addition to its role in forming haplotypes have led to the identification of the mucosal surface barrier, the epithelial cell several more susceptibility genes, including compartment has key capabilities of innate those encoding the receptor for the cytokine immune response, including expression of IL-23 and ATG16L1, a protein involved in both Toll-like receptors (TLRs) and NODs the process of autophagy and several other and production of effectors, such as defensins. processes. Identification of these genes has These may be central to the functional outcome focused mechanistic studies on the processes of contact and interaction with luminal that they may mediate, including innate microflora—both commensal populations and immune response to bacteria and regulation enteric pathogens. Alterations in these factors of adaptive immunity. More comprehensive and processes are found in IBD. understanding may allow a clinically useful definition of disease risk and prediction of IBD involves the loss of mechanisms that disease course and response to therapy. normally ensure peaceful coexistence with luminal microflora Commensal microflora as key drivers of intestinal inflammation Despite possessing a robust variety of receptor and signaling pathways that should trigger Extensive efforts have failed to consistently inflammation in the context of ubiquitous implicate a specific pathogen in association and constant contact with microflora, the with IBD. However, murine models and epithelium remains in a state of “tolerance” or circumstantial observations in patients hyporesponsiveness. While this hyporesponsive provide compelling evidence that the complex posture allows peaceful co-existence with the variety of commensal microflora, which is

98 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases omnipresent luminal microflora, it points to Relative functional deficiency of the latter important questions for further study, such as: appears to enable the ongoing inflammation. how is this state abrogated in circumstances Dendritic cells and the pivotal role they where inflammation may be a normal and have in priming these responses have also healthy response (e.g., exposure to a true been defined. Finally, a multitude of cytokine enteric pathogen); and how is it altered in products of these cell populations and others the context of IBD in the absence of a have been identified and their functional specific pathogen? effects delineated with the demonstration that many may be particularly important in the Processes mediating innate immune pathogenesis of IBD (including, among others: responses and alterations associated IL-1, IL-2, IL-12, IL-17, IL-23, TNF, interferon, with IBD and TGF-β).

The finding that the IBD1 genomic region Clinical effectiveness of mechanism-based contains a gene encoding an intracellular therapeutic agents innate immune receptor protein, as well as the characterization of the full spectrum of Although therapy remains inadequate for receptors, their signaling mechanisms, and many patients and none is curative, anti-TNF effector mediators, underscores the importance treatment has been shown to effect substantial of these pathways in mediating normal response in some patients who do not respond mucosal homeostasis and alterations that can adequately to other modalities. Other agents lead to IBD. The former advance relates to targeting mediators and mechanisms identified regulation of intracellular bacterial survival through recent studies on IBD pathogenesis and production of the antimicrobial defensin appear promising in clinical trials. proteins, and the latter relates to altered NOD and TLR receptor forms in patients with IBD. Mediators of inflammation and These receptors appear to play a central role tissue injury in the initial responses to luminal bacteria and, ultimately, result in chronic intestinal As noted above, many cytokines have been inflammation with downstream activation of found to mediate activation of different adaptive immunity. cell populations. These cells, in turn, produce a variety of non-peptide effectors of Processes that effect adaptive mucosal inflammation that include leukotrienes and immune responses and their alteration other -derived products, as well associated with IBD as reactive oxygen metabolites. These appear to be among the most proximate mediators of Researchers have identified several key tissue damage. lymphocyte populations and their cytokine products that drive ongoing intestinal Mechanisms of mucosal tissue repair inflammation through stereotypic responses. and fibrosis In addition to the long-recognized Th1 and Th2 responses, these are now known to include Many manifestations of IBD can be traced to Th17 lymphocytes driven by IL-23 and capable either failure of normal repair mechanisms to of producing IL-17, which leads to release of restore mucosal integrity or pathologic repair pro-inflammatory cytokines by target cells processes that result in fibrosis and loss of and tissue injury, as well as a constellation of normal physiologic function. Key components FoxP3-positive and -negative regulatory cells. of mucosal repair processes, including the

Inflammatory Bowel Diseases 99 contribution of trefoil peptides and some select Murine models of colitis cytokines, have been identified. Alterations in the balance of production and degradation of Many advances in delineation of processes extracellular matrix constituents, including the relevant to IBD have been made possible metalloproteinases and the factors that modify through the development of murine lines them (e.g., TIMPs), have been observed in modified by either targeted gene deletion association with fibrosis in IBD. Definition of key or transgene expression that experience components of the coordinated repair response to “spontaneous” colitis. These animal models have injury and the ability to enhance repair through been used to demonstrate that colitis can result novel strategies for delivering recombinant from functional alterations in the epithelial proteins will play an important role in advancing compartment and certain immune processes. The understanding of IBD, as highlighted by studies models have also allowed researchers to explore of trefoil peptides. These may enable new the interaction between genetic susceptibility therapeutics for IBD, complementing those and environmental factors, including the role of targeted to inflammatory processesper se, luminal microflora. which may also have particular importance as prophylactic interventions. goalS For rESEarcH

GOALS FOR RESEARCH 11

Research Goal 5.1: Establish an objective criteria that can guide diagnosis and management. basis for determining clinical diagnosis, detailed Similarly, the rapid evolution of imaging technology phenotype, and disease activity in IBD. reflecting pathophysiologic processes provides an opportunity for functionally meaningful assessment Despite decades of clinical experience, diagnosis of disease activity. Finally, identification of suitable of the major forms of IBD remains dependent disease markers that permit objectivity and on empiric criteria that leave important residual consistency in diagnosis and subclassification of uncertainty in a significant minority of patients. patients will facilitate and enhance the efficiency of Further, despite the well-recognized spectrum clinical trials. of clinical manifestations, objective means are not available to substratify patients in order to Objectives: predict the natural history of disease or likely ß Develop a comprehensive genotypic profile. responsiveness to different therapeutic agents ß Define informative immunophenotypic profiles. that would facilitate more effective and efficient ß Develop methodology and applications for a therapy. Progress in defining genotypes associated microbiomic profile. with disease susceptibility, identifying markers of ß Develop technology for effective anatomic immune response, identifying the central role of and functional imaging of disease location and luminal microflora, and defining themicrobiome of activity. individuals supports the development of rigorous ß Establish useful correlative and predictive and prospective studies to validate objective biomarkers.

11 Research Goals are numbered for ease of reference only; the numbers do not indicate prioritization of scientific topics.

100 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Goals for Research

Research Goal 5.2: Develop an individualized Research Goal 5.3: Modulate the intestinal approach to IBD risk evaluation and management microflora to prevent or controlIBD. (See also Goals based on genetic susceptibility. 1.20, 1.21, and 9.3.)

While significant progress has been made in The convergence of insights derived from identifying genetic risk factors for IBD in some experimental and clinical observations points to a broad populations, substantial limitations remain central role of the luminal microflora as a driver of in applying these insights to individuals. Study chronic IBD. While research proceeds in defining populations to date have not delineated the host factors that contribute to the development relative risks within subpopulations that reflect of an immune and inflammatory response that the full diversity of people who may be affected. overrides the tolerance to luminal microflora Most importantly, substantial gaps remain in found in healthy individuals, understanding of the understanding the interaction between acquired or complex populations of microbes that constitute environmental factors to determine the mechanisms the luminal microflora is markedly incomplete. leading to actual IBD development within Beyond the intrinsic complexity of the microflora, individuals. Achieving this overall goal requires a a major barrier to defining the combination of complete understanding of the functional effects of microbes and/or their products that are important the variant genes that have been found to confer in the pathogenesis of IBD in populations and risk of IBD, as well as a comprehensive matching individuals is the inability of current technologies of disease-associated genotypes to disease features to resolve this complexity. Development of large- and response to therapy. Genes that metabolize scale sequencing and corresponding powerful agents used in the management of IBD need to computational tools is essential to understanding be investigated with respect to their influence in the role of the microflora in IBD pathogenesis. modulating response to therapy and potential Insights derived from the application of these tools toxicities. Undertaking a multi-dimensional and can also provide a foundation for the development comprehensive study of IBD-associated genes and of strategies for effective therapeutic manipulation their products is a critical component of this goal. of luminal microflora content, which conceptually should be free of risk for adverse side effects. Objectives: ß Complete identification ofrisk susceptibility Objectives: genes among diverse patient populations. ß Achieve a comprehensive molecular and ß Determine the functional role of IBD-associated functional delineation of the intestinal gene variants in pathophysiologic pathways microflora in all relevant niches across different leading to IBD. individuals/populations. ß Determine the impact of environmental factors ß Understand the factors that regulate the on disease-associated genetic variants. composition and functional characteristics of the ß Define genetic subset/phenotype-genotype intestinal microflora, including host factors (e.g., correlations. environmental, genetic, and mucosal function). ß Identify and assess relevant pharmacogenetic ß Characterize the intestinal microflora associated variations. with IBD by location and disease activity. ß Correlate genotype (disease susceptibility and ß Develop experimental tools for understanding pharmacogenetics) with response to therapy and intestinal microbiome complexity and clinical incorporate genotypes into clinical trials. methods for characterization and monitoring of ß Use genotypic variations to define diseaserisk. the intestinal microflora in patients.

Inflammatory Bowel Diseases 0 Goaloalss for for Rese Rarcesearchh

ß Develop experimental in vivo systems for ß Delineate innate and adaptive immune preclinical studies of intestinal microflora interaction with the microbiome. therapeutic modulation. ß Identify relevant inflammatory mediators in effecting IBD injury and symptomatic manifestations of IBD and mechanisms Research Goal 5.4: Effectively modulate the regulating inflammatory processes. mucosal immune system to prevent or ameliorate IBD. ß Characterize alterations in innate and adaptive immune function in IBD, including It is axiomatic that immune activation and the regulatory cell populations, especially related to production of inflammatory mediators are intrinsic microbiome. to IBD, in which the presence of infiltration with cells associated with these responses is among the defining empiric criteria of these disorders. Research Goal 5.5: Sustain the health of the Substantial progress has been made in defining mucosal surface. the components of mucosal innate and adaptive immune responses. However, a comprehensive Normal intestinal function depends on the integrity understanding of these complex pathways is still of the mucosal surface. Research indicates that the needed as a foundation for understanding their epithelium may be intrinsically altered by genetic activation and alteration in the context of IBD. This and other factors that play a role in the initiation will require developing molecular signatures of all of IBD. Conversely, the epithelium is the victim of immune cell populations, the factors regulating the inflammatory processes that lead to mucosal their activation, and their products. The intricate ulceration, a central process underlying IBD that interconnection among the cell populations permits sustained activation of underlying immune participating in immune and inflammatory responses and inflammatory responses. Understanding the and the multiplicity of their products demands a biology of the epithelium will provide insights into systematic approach and the quantitative strategies the earliest and most central events that lead to of systems biology. Given the mounting evidence the major forms of IBD and create a foundation for the pivotal role of luminal microflora inIBD, it is for developing strategies to enhance the functional essential to delineate the interactions among these and physical integrity of the mucosal surface. flora, the immune response, and the factors that Defining the role of the epithelium in these deregulate the processes that allow tolerance in the disorders depends on integrated study of the normal intestine. Determining the total components interaction of this surface compartment with the of the immune and inflammatory response should luminal microflora at its apical surface and the enable the development of strategies for focused variety of cell populations within the underlying modulation to achieve effective control of these lamina propria. It is equally important to define responses without the toxicities that result from the the distinct roles of the four major cell lineages relatively non-specific and broad immunosuppressive (columnar, goblet, Paneth, and enteroendocrine) effects of most current therapies. that collectively comprise the epithelium, given that functional alterations in each cell type are Objectives: associated with IBD. Investigating the intestinal ß Define all relevant immune cell populations stem cell compartment and the processes by their functional characteristics and regulating the production and differentiation of differentiation pathways. cells emerging from progenitor populations is an ß Define the factors regulating innate and adaptive important aspect of this goal. immunity, both genetic and environmental.

102 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Goals for Research

Objectives: Objectives: ß Understand the functional biology of the ß Understand normal repair processes and epithelial compartment and identify alterations characterize their alteration in IBD. in IBD. ß Define the impact of the intestinalmicroflora on ß Identify and characterize the stem cell tissue repair. compartment and develop the capacity to ß Develop strategies to modulate repair processes modulate lineage specification and maturation. to restore functional capacity. ß Understand the structural and functional ß Identify mechanisms to reverse or remodel elements of the mucosal barrier, including the fibrotic response. role of luminal microflora and nutrients, and ß Identify interventions that improve care of alterations associated with IBD. patients with surgically modified gut. ß Define thesystems biology of the intestinal mucosa, including interactions among epithelial and lamina propria cell populations, as well as Research Goal 5.7: Provide effective tools for integration with enteric nervous, endocrine, and clinical evaluation and intervention in IBD. vascular elements. While prevention of IBD is the ultimate goal, more effective tools for the evaluation of disease activity Research Goal 5.6: Promote regeneration and are needed to guide therapy, and more effective repair of injury in IBD. therapeutic agents are needed for the many patients for whom currently available modalities are In parallel with the goal of sustaining the health of ineffective or counterbalanced by adverse effects. the mucosal surface, effective treatment of patients New tools should include noninvasive modalities for with established IBD will utilize insights in mucosal rapid assessment of the distribution and intensity of biology to promote repair of injury resulting from inflammatory activity. Identification of early markers inflammatory processes. Such therapies should of inflammation, as well as markers that predict aim to restore structural integrity and physiologic ultimate response soon after initiation of a new function to affected sites within the GI tract. For therapeutic intervention, will be powerful adjuncts many patients, the morbidity of their disease results to both routine clinical management and a means more from the failure of healing with ongoing of accelerating the speed and efficiency of clinical ulceration or a pathologic healing response and trials of new agents. Finally, it is essential that resultant fibrosis and/or loss of mucosal function evolving insights into the critical pathophysiologic than from the effects of inflammationper se. mechanisms that lead to IBD are used to develop Effective interventions to promote physiologic more specific therapeutic agents and other repair will depend on knowledge of the processes interventions that fill the unmet treatment needs of that contribute to tissue healing. Understanding the IBD patients. factors contributing to fibrosis and the mechanisms that allow remodeling of the extracellular matrix Objectives: will be particularly important given the frequency ß Develop and validate technologies to evaluate at which fibrosis leads to obstruction and other disease status, including biomarkers, as well morbidity. Strategies to improve functional capacity as noninvasive and other novel endoscopic are also important for the many patients in whom imaging methods. the disease process leads to extensive mucosal ß Develop innovative endoscopic and more destruction, as well as the many others who physiologic surgical interventions. currently require extensive surgical resection.

Inflammatory Bowel Diseases 0 GOALS FOR RESEARCH

ß Develop effective and non-toxic mechanism- This impact extends from limitations in physical based pharmacologic therapies, including stature to difficulties in social and emotional manipulation of the microflora. maturation that can follow. These potentially ß Develop tools for more efficient clinical profound effects on growth reflect a variable development of investigational agents, combination of the influence of inflammatory including surrogate markers of response. mediators, malabsorption resulting from mucosal ß Develop tools to more effectively identify pre- injury, and poor nutritional intake. In addition malignant changes in the mucosa and support to the effects of IBD, drugs used to treat the interventions to reduce cancer risk. disease may have a negative impact on overall growth. Accordingly, strategies are needed to ensure normal growth and development in these Research Goal 5.8: Ameliorate or prevent vulnerable patient groups, in concert with overall adverse effects of IBD on growth and efforts to treat the IBD. development in children and adolescents. Objectives: In addition to the challenges faced by adult ß Develop interventions that promote normal patients with IBD, children and adolescents face social interactions and mental health in all distinctive clinical manifestations unique to these children and adolescents with IBD. patient groups due to the potential impact of ß Define the mechanisms that produce growth the disease on normal growth and development. delay in pediatric IBD patients. Indeed, the lack of growth can be the most ß Identify approaches that enable normal growth prominent manifestation in childhood, and the and development within the context of failure to undergo a normal growth spurt in young pediatric IBD. adolescents with IBD has potential lifelong impact.

MAJOR CHALLENGES AND STEPS high-throughput techniques to define TO ACHIEVE the RESEARCH GOALS individual members of complex microbial communities, robust bioinformatic tools, and Basic mechanisms of IBD: To build on metagenomic data sets with comprehensive recent progress in defining IBD susceptibility data on provenance and host phenotype genes, large-scale collaborations (national would accelerate progress in the field. and international) would facilitate New computational tools, such as in silico comprehensive sample acquisition, analysis techniques for modeling microbial populations of genetic loci across diverse populations, and microbial-host interactions, would enable and research on well-characterized patients researchers to effectively mine extremely large followed on a longitudinal basis to define data sets. Initiating an intestinal microbiome genotype-phenotype correlation. Even more project, beginning with commissioning challenging are the current methodological computational tools and pilot projects, limitations for the study of complex microbial represents an important step to addressing populations in the GI tract. The development these challenges. The establishment of the and dissemination of rapid, quantitative, Human Microbiome Project within the NIH

104 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Roadmap for Medical Research provides patients remains a significant barrier. Fully essential technologies and resources for realizing the opportunities to develop and research on the intestinal microbiome. An evaluate new therapies based on growing equally important and technically difficult insight into IBD pathophysiology depends hurdle is the development of techniques on establishing standards for clinical to isolate and sustain primary epithelial trials, including incorporation of surrogate cell populations in vitro to enable research endpoints, phenotyping, and DNA collection. on these critical cell populations and their Standardization of techniques for DNA sample functional alteration in IBD. acquisition would also foster close integration with translational studies. Overall, the Translational research: With acceleration potential synergies between clinical studies of the discovery of susceptibility genes and and translational analysis have not been basic mechanisms of immune response and realized and, thus, provide an opportunity to epithelial function, the opportunities for accelerate the assessment of basic mechanisms translational research in the context of IBD elucidated through study of animal models and are greater than ever. In order to realize in vitro systems within the context of human the potential for new insights into disease IBD. Equally important, development of more processes, it is important to develop robust effective strategies for enrolling patients in in vitro model systems, including primary clinical trials and fostering the development cell and organ cultures, that recapitulate of a larger cadre of clinical investigators and the complexity of intestinal mucosa and can clinical trial infrastructure would support be experimentally manipulated. Parallel an expanded national and international development of animal models with validated program of interventional clinical trials for clinical relevance in which response to IBD. Particular attention should be paid to intervention is predictive of response in overcoming barriers to therapeutic trials humans would enable rapid progress from in pediatric populations, such as industry in vitro systems to animal model studies reluctance due to potential risks in these to patients. Better integration of basic and patient groups. These efforts, as well as more clinical research efforts is essential for more basic and translational research challenges, effective translational progress. Establishing would benefit substantially from greater public consortia of investigators across institutions awareness and understanding of IBD that would expedite research to understand the can be achieved through public educational functional implications of the gene variants programs. Convening a clinical summit on IBD that have been associated with IBD. attended by investigators, all stakeholding agencies, and industry would be an initial step Clinical research and discovery: The toward surmounting these challenges. lack of objective and consistent criteria for diagnosis and substratification of

Inflammatory Bowel Diseases 0 Illustration showing the proposed origin of various small bowel epithelial cell types from possible stem cells located at the base of the crypts. Stem cells play an important role in regenerating the intestinal epithelium.

Image courtesy of Dr. Nick Barker. Reprinted from Gastroenterology, 133, Barker N and Clevers H, Tracking down the stem cells of the intestine: strategies to identify adult stem cells, pp. 1755-1760, Copyright 2007, with permission from Elsevier.

0 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Intestinal Failure and Regeneration, Nutritional Disorders and Support, Surgically Modified Gut, and Transplantation

SUMMARY OF RESEARCH GOALS

Loss of intestinal function can occur through surgical removal of tissue or diseases that impair digestion or cause tissue death. The Commission recommends research goals that, if pursued, would increase understanding of the natural mechanisms of growth, differentiation, and adaptation in the gastrointestinal (GI) tract and use that information to better treat patients with GI diseases. Research is needed on the development of new treatment strategies for short bowel syndrome (SBS) and intestinal failure, including innovative approaches to optimizing intestinal transplantation and post-transplant survival. GI tract surgeries, including bariatric surgeries for weight loss, are frequently associated with nutritional or hormonal complications. An important research focus is improving nutritional support for surgical patients and others with digestive diseases who rely on parenteral or enteral nutrition to sustain life, including premature infants with necrotizing enterocolitis (NEC). Achieving these research goals would markedly enhance the quality of life and health of many patients with digestive diseases or injury who are unable to properly absorb nutrients through their GI tract.

Intestinal Failure and Regeneration, Nutritional Disorders and Support, Surgically Modified Gut, and Transplantation 0 INTRODUCTION AND BACKGROUND to severe SBS often develop intestinal failure, which results when there is insufficient The collection of topics in this chapter is linked intestine to absorb adequate fluid to maintain by a common interest in the physical integrity hydration and/or to absorb 85 percent of of the gut and strategies to promote natural required nutrients. These patients require repair and regeneration processes in response intravenous fluids, , or nutrients to loss of intestinal tissue function through through such means as parenteral nutrition surgery or disease. (PN)—the delivery of nutrients and fluids by rather than by ingestion to sustain Intestinal growth and differentiation: At life. Unfortunately, with prolonged use, PN is birth, the human small intestine is typically associated with life-threatening complications. 2-3 meters in length and grows to about 6-7 meters in adults. In addition, the epithelial For fortunate patients without massive gut loss, lining of the intestine is continually renewed SBS is a temporary phenomenon. Intestinal as new cells mature from proliferating stem adaptation can occur by enlargement of cells located at the base of the intestinal the intestinal villi, an increase in crypt cell crypts. This lifelong capacity for growth proliferation, or an increase in the diameter of and differentiation of the complex cellular the small intestine—all of which augment the structure of the intestine suggests the surface area available for nutrient absorption. potential for development of regenerative cures Alternatively, slowing of peristalsis—the for many digestive diseases as researchers movement of food through the digestive learn how to identify, isolate, and manipulate tract—can also help patients adapt to a shorter intestinal stem cells. intestine. These processes can be facilitated with luminal nutrients and growth factors, Short bowel syndrome and intestinal although a much better understanding of these adaptation, repair, and regeneration: factors is needed to optimize this therapy. SBS can occur when half or more of the small Finding ways to promote intestinal adaptation, intestine is missing or not functioning properly. repair, or regeneration could lead to new Infants and children can develop this condition therapies for SBS in both children and adults. for a variety of reasons, including congenital PN failure occurs in some patients from loss defects and NEC. In adults, SBS can result from of venous access as a result of central vein surgical removal of the intestine for treatment thrombosis, recurrent severe septicemias, or of inflammatory, mechanical, and malignant development of irreversible liver disease. These processes, including Crohn’s disease, tumors, patients require small bowel transplantation. (a twisting of the intestine that causes A combined liver/small bowel transplant tissue death), , traumatic is necessary when liver failure occurs in injury, or other conditions. Patients with this conjunction with intestinal failure. syndrome develop diarrhea, dehydration, and malnutrition due to the inability of the intestine Intestinal transplantation: For patients to absorb sufficient water, , minerals, with irreversible intestinal failure or those and other nutrients from ingested food. with progressive complications of PN, small intestine transplantation is the last therapeutic Patients with mild SBS are treated with option. Close to 200 intestinal transplantations, dietary modification (small frequent meals), either alone or in combination with other with or without anti-motility and anti- abdominal organs, are performed each year in secretory medications. Patients with moderate the U.S. The short-term success of intestinal

108 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases transplantation procedures is now similar to micronutrients to dehydration and starvation that for other solid organs (close to 80 percent in extreme cases. Some patients, such as those 1-year survival for host and graft) due to recent with anorexia or dysfunction of the upper advances in immunosuppression, and recent GI tract, can be treated by enteral feeding studies suggest successful transplantation is through a tube placed directly into the GI associated with improved quality of life. Long- tract. If all gut function is lost, as for patients term survival, however, remains suboptimal. with moderate to severe SBS and intestinal failure or in premature infants with NEC, PN Metabolic and nutritional consequences supports survival. Specialized enteral diets of surgically modified gut: With the and gut peptide analogues, such as glucagon- increasing prevalence of obesity in the U.S. like peptide-2 (GLP-2) and growth hormone, and worldwide, bariatric surgical procedures can maximize mucosal adaptation and are becoming more common in both adults regeneration. However, complications of PN for and adolescents. Different surgical procedures patients needing long-term nutritional support are used, with the most frequent being a can include infections, chronic liver failure, reduction in stomach size, bypass of a portion loss of kidney function, metabolic bone disease, of the small intestine, or a combination and blood clots. of both strategies. Many patients achieve significant weight loss in response to the surgery, although serious complications at RECENT RESEARCH ADVANCES the time of surgery, such as anastomotic leakage, pneumonia, deep vein thrombosis Mechanisms regulating mucosal function and , or death, can occur in rare and growth cases. Serious chronic side effects also may follow bariatric surgery procedures, including The mechanisms responsible for regulating intestinal infections, food intolerance, , mucosal function and growth have been and the need for surgical revisions or surgery clarified at the cellular and molecular levels, for treatment of complications, occasionally allowing for manipulation of the intestinal resulting in intestinal loss. Nutritional milieu in order to augment intestinal deficiencies can occur due to poor absorption of adaptation. For example, growth factors have food and vitamins or minerals in the modified been shown to enhance villus growth, stimulate gut. Weight loss after bariatric surgery is not enterocyte proliferation, and attenuate wholly explained by restricted food intake, enterocyte apoptosis in the remnant gut but may also involve metabolic and hormonal following massive intestinal resection. Animal changes resulting from the surgery that are investigations, as well as preliminary studies in not yet fully understood. humans, suggest that growth factors, including GLP-2, insulin-like growth factor-1 (IGF-1), and Nutritional support of patients with epidermal growth factor, may help stimulate GI disorders :12 Patients with GI disorders intestinal growth and development and lead often develop nutritional deficiencies due to improved fluid and nutrientabsorption. to interference with the normal digestion Collectively, these growth-stimulating and absorption of food, ranging from mild phenomena in animal models are termed post- deficiencies resulting from poor absorption of resectional adaptation. Work over the last two

12 The Commission considered the issue of nutritional support and its consequences for patients with gastrointestinal diseases. However, the broader topic of nu- tritional research planning is overseen by an existing group, the NIH Nutrition Coordinating Committee within the Division of Nutrition Research Coordination.

Intestinal Failure and Regeneration, Nutritional Disorders and Support, Surgically Modified Gut, and Transplantation 0 decades has demonstrated that this process is to minimize malabsorption, it has been influenced by a number of factors, including demonstrated that intestinal lengthening specific luminal nutrients, such as fiber, as well procedures, including serial transverse as a variety of GI and systemic hormones and enteroplasty (STEP) and the Bianchi peptides. These studies have demonstrated that procedure to remove non-functional and luminal nutrients and bacteria are capable of dilated loops of the intestine, lead to improved altering gene expression profiles andabsorption intestinal function, including absorption of and digestion in enterocytes. The availability nutrients and liquids. and study of isolated enterocytes and enterocyte cell lines have clarified the specific role of Intestinal transplant registry peptides, hormones, and matrix factors on these growth and differentiation processes. Advances in intestinal transplantation have been documented by data from establishment The chronology of intestinal adaptation has of a voluntary international intestinal demonstrated that the gut is most responsive to transplant registry. The registry includes stimulation and augmented growth immediately virtually all intestinal, intestine/liver, and following the loss of intestinal surface area. multivisceral transplants performed around Both animal and human models demonstrate the world. Expansion of the registry has that growth hormone, but not glutamine, may allowed accurate appraisal of patient survival, enhance intestinal adaptation and improve fluid graft survival, impact on survival of PN use, and nutrient absorption, leading to the ability to and other outcome data. The collaborations reduce PN requirements. Recent translational that contribute to the ongoing registry project studies in patients with SBS-intestinal failure have facilitated improved management of have shown promise for efficacy of novel agents patients and development of new collaborative and medications not originally developed for research projects by international centers of GI conditions. The adaptive processes of villus excellence in intestinal transplantation. hypertrophy and improved fluidabsorption, with the reduced need for PN, can be enhanced with Intestinal transplantation GLP-2 and GLP-2 analogues. Improved chloride and fluidabsorption has been reported with Intestinal transplantation, with or without orally administered or transdermal clonidine. the liver, has become progressively more successful in the major transplant centers, with The identification of a stem cell niche with first-year survival rates similar to orthotopic specific responsiveness to growth factors, gut liver transplantation alone. The improvement peptides, and paracrine factors has enhanced in quality of life is substantial for patients our understanding of specific molecular with intestinal failure who are dependent on features of this growth adaptive process. permanent PN. This occurs in the majority of, but not all, graft recipients. Definition of Surgical modification of thesmall intestine factors contributing to graft survival, optimal management of immunosuppressive regimens, Intestinal lengthening procedures have led improved methods to monitor rejection, to improved management of infants and and factors contributing to adaptation of children with refractory SBS. Intestinal the transplanted gut remain areas of active dilation, bacterial overgrowth, and luminal investigation. It has also been observed that stasis are hallmarks of chronic SBS in infants intestinal transplantation can not only prevent, and children. Refractory to medical strategies but also reverse, early PN-induced liver

110 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases dysfunction, thus avoiding the eventual need for Effect of parenteral nutrition on combined small bowel/liver transplantation. GI development

Candidate markers for intestinal transplant Several strategies to reduce the negative rejection without the need for tissue biopsy impact of PN on developing GI organs have been identified, including 3-0-methyl have been identified. PN may cause glucose absorption, serum citrulline, and deficiency, which has been implicated in calprotectin. Each may potentially serve as a fatty liver, an early step in liver disease. surrogate for intestinal mass and/or rejection Intravenous choline supplementation may and, thus, avoid the need for frequent intestinal ameliorate this process. -based , biopsies to identify early reversible rejection. tumor necrosis factor (TNF) blockade, cycling Tolerance to the intestinal graft develops in of PN, and ursodeoxycholic acid administration some patients, allowing a reduction in immune have been reported to possibly be of benefit in suppression to a few times per week. Factors the treatment of PN-associated liver disease. responsible for the development of tolerance are The timing of introduction of enteral feedings unclear and are being investigated. or PN in neonates and premature infants has demonstrated that there are critical Regenerative medicine for treatment of windows to optimally introduce these factors to intestinal failure maximize GI development, infant weight gain, and growth. Mucosal plugs from the intestinal stem cell niche have been successfully grown on Prevention and treatment of NEC bioartificial scaffolds. Placed in continuity with the native intestinal tract, these mucosal NEC remains one of the most lethal perinatal plugs have demonstrated normal proliferative conditions of premature, low birth weight patterns and the capacity to expand to infants. Prevention is the key objective fill gaps in the intestinal mucosal surface. for, once established, this condition is the Given the dense lymphatic tissue burden lead cause of intestinal failure in children. in intestinal allografts, the ideal long-term Preliminary data from trials in premature solution for patients with intestinal failure infants suggest that probiotics may be will be a regenerative medicine approach in beneficial in the prevention of NEC, and which native intestinal tissue is expanded granulocyte stimulating factor may reduce on a suitable scaffold and grown to a size progression to more severe NEC. Surgical and surface area sufficient to support enteral approaches have also been introduced nutrition when placed in continuity in the GI to minimize the role of resection in the tract. Identification of the stem cell niche and management of these patients while ensuring expansion of this population into a mature and adequate management of abdominal sepsis in differentiated mucosal surface is an important these critically ill infants. first step in this process. Identification of appropriate matrix, manipulation of the Intestinal microflora growth and differentiated environment, and strategies to induce vascularization sufficient The application of DNA methodology to to incorporate the tissue into the native GI assess the resident bacteria of the gut has tract will be required to achieve a tissue- revealed tremendous diversity and mass of the engineered solution. microflora. These studies have opened

Intestinal Failure and Regeneration, Nutritional Disorders and Support, Surgically Modified Gut, and Transplantation 111 up research on the role of bacteria in the indicate that substantial changes in metabolic prevention and causation of intestinal and GI hormones occur. Identification of disorders, including those that may lead to the mechanisms underlying surgically SBS-intestinal failure. induced weight loss in animal models could result in development of medical means to Animal models of bariatric surgery produce significant and durable weight loss, which is currently achievable only through A rat model of gastric banding has been surgery. Animal models may also allow better developed, and bariatric surgical mouse understanding of the long-term metabolic models have also been developed. While sequelae of bariatric procedures, including mechanical mechanisms were once considered specific nutrient deficiencies, metabolic and the primary modality of weight loss, recent bone disorders, management of bypassed advances in measurement of gut hormones, segments, and other issues. including ghrelin, polypeptide Y, and others,

GOALS FOR RESEARCH 13

Research Goal 6.1: Define mechanisms of Objectives: intestinal growth and differentiation. (See also ß Isolate, characterize, manipulate, and expand Goal 1.6.) human intestinal stem cells in vitro. ß Define optimal growth factors, nutrients, The intestine has the capacity to grow during extracellular matrix, and milieu to enhance childhood, renew its lining throughout life, and post-resectional adaptation in human patients. adapt to loss of mucosal surface area due to ß Develop an optimal bioartificialscaffold for surgical resection or disease. By understanding neomucosal growth. these processes at a molecular and cellular level, it ß Develop artificial intestinal constructs for might be possible to develop new pharmaceutical replacement of diseased bowel. or cell-based therapies to enhance these natural ß Conduct a clinical trial of exogenous factors to phenomena, either to (1) effect total remission optimize post-resectional adaptation. or cure of disease by replacing sections of the intestine with functional tissue; or (2) promote recovery from surgery or injury by stimulating Research Goal 6.2: Develop new strategies to endogenous repair pathways. Researchers are treat short bowel syndrome and intestinal failure. focused on characterizing the mechanisms that govern lineage selection of cell phenotypes Surgical bowel resection for conditions such from intestinal stem cells and understanding as Crohn’s disease or injury can lead to the the molecular pathways involved in intestinal development of SBS or intestinal failure, although adaptation. some adaptation of the remaining tissue is possible.

13 Research Goals are numbered for ease of reference only; the numbers do not indicate prioritization of scientific topics.

112 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Goals for Research

Studying the nutritional, hormonal, or other Moreover, new techniques are needed to monitor factors that promote adaptation could reveal organ rejection that would be less invasive than new strategies for enhancing bowel recovery conventional endoscopic biopsy. from surgical resection. Avoidance of SBS and intestinal failure would represent a significant Objectives: therapeutic advance and relieve the significant ß Determine the role of exogenous growth factors medical and economic burden of these conditions. and micronutrients post-transplantation. Further research is needed to understand why PN ß Improve methods for donor bowel preservation complications arise and how they can be prevented pre-transplant. and/or treated. ß Identify new targeted pathways for novel immunosuppressive therapies. Objectives: ß Develop artificial intestinal conduits from native ß Evaluate the effect of specific micronutrients and tissues and cells for autotransplantation. diet on post-operative intestinal adaptation. ß Identify biomarkers for noninvasive diagnosis of ß Develop and validate noninvasive markers of intestinal transplant rejection. intestinal growth and adaptation in models of SBS. ß Identify factors that diminish long-term post- ß Develop reliable, noninvasive methods to measure transplant survival and develop appropriate intestinal growth and adaptation in patients. countermeasures. ß Develop more effective techniques and strategies to reduce septic, metabolic, thrombotic, and hepatic complications of PN and intestinal failure. Research Goal 6.4: Understand and treat ß Define the molecular basis of radiation the metabolic and nutritional consequences of and of potential approaches to prevent and bariatric procedures and other surgical modifications treat radiation enteritis and proctitis. of the gut. ß Conduct a clinical trial of optimal growth factor (or synergistic combination) therapy following Bariatric surgery for weight loss and other massive intestinal resection. surgical modifications of the gut have metabolic ß Develop prognostic indicators for PN failure and hormonal consequences that were not to guide the timing of intestinal transplant originally predicted based on simple resection of evaluation in optimal candidates. tissue. Researchers are working to understand the molecular bases for these phenomena and use these insights to develop non-surgical Research Goal 6.3: Improve the success of interventions to achieve the same result. Further, intestinal transplantation. knowledge of these pathways could aid in the identification of biologic markers that predict Intestinal transplantation can be a life-saving which patients are most likely to benefit from treatment for some patients with intestinal bariatric or other surgeries. failure who have developed potentially life- threatening complications. The success of this Objectives: procedure could be improved by developing novel ß Identify pre-operative biomarkers to predict immunosuppressive drugs that are tailored for weight loss and metabolic correction. the unique immunological milieu of the intestine ß Characterize the neuroendocrine, hormonal, or by optimizing organ selection and preparation cytokine, and proteomic responses to bariatric to minimize the risk of rejection and infection. procedures in animal models and humans.

Intestinal Failure and Regeneration, Nutritional Disorders and Support, Surgically Modified Gut, and Transplantation 113 GOALS FOR RESEARCH

ß Characterize the long-term metabolic (vitamins, understand the impact of nutritional support calcium, minerals, other) sequelae and changes protocols on patients’ daily lives, to improve the in anorexic and orexigenic hormones in bariatric nutritional value of these treatments, and to reduce surgical patients. the risks of adverse events. ß Develop non-surgical therapy that “mimics” neurohumoral sequelae of bariatric procedures. Objectives: ß Develop specific dietary guidelines for patients ß Develop and validate quality-of-life measures undergoing bariatric and other surgical for patients with chronic GI dysfunction to modifications of the gut that can effectively allow assessment of the efficacy of different prevent adverse metabolic and nutritional treatments. consequences based on newly identified ß Evaluate the effect of specific micronutrients hormonal and absorptive abnormalities. and diet on GI absorption, motility, and immunity. ß Evaluate the importance of the gut microflora in Research Goal 6.5: Optimize nutritional the prevention and causation of GI diseases. support of patients with GI disorders. ß Determine optimal micronutrient requirements for patients that require long-term PN, as well as Many patients with severe GI dysfunction, including for those with catabolic illness that require PN. premature infants, rely on enteral or parenteral ß Assess the safety and potential efficacy of nutritional support to sustain life. Although these prebiotics, probiotics, and symbiotics in the procedures are indispensable for many patients, prevention of NEC and -related sepsis. they carry the risk of severe side effects and do not ß Design and test diet formulations to prevent perfectly replicate normal digestion and absorption neonatal feeding intolerance and NEC. of nutrients. Further research is warranted to

MAJOR CHALLENGES AND STEPS with small intestine allografts would facilitate TO ACHIEVE the RESEARCH GOALS recruitment of patients for clinical research and intervention trials. Finally, centralized National research resources: Translational tissue banks of biosamples from patients and clinical research on intestinal failure with different GI disorders or those who are and regeneration and related issues are undergoing bariatric surgery and follow-up hampered by the small numbers of patients would enable researchers to readily access at any single institution. In addition, many human tissues for research, regardless of the investigators have difficulty accessing human location where the patients received care. intestinal tissue at the time of resection or at regular intervals after adaptation. The Standardized clinical definitions: establishment of multicenter clinical and basic Development of a standardized system to research networks would promote progress characterize SBS and intestinal failure in in the field by fostering collaboration and terms of anatomy, nutritional support, and sharing of resources. A national registry for complications is an important challenge for SBS-intestinal failure patients and for those the field. Having such a system would enable

114 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases researchers to directly compare data and Advanced technologies: The difficulty in outcomes across studies and patient groups. accessing the small bowel with repetitive Achieving consensus on data points, definitions, surgical or endoscopic procedures hampers and outcome measures would facilitate both clinical research and patient care. understanding of the relative effectiveness of The development of novel, less invasive medical, nutritional, and surgical intervention technologies to access the intestinal lumen strategies. ICD-9 codes should be created and would stimulate research on human disease. implemented to assist in the tracking of afflicted Furthermore, identification of serum or patients. Creation of a health outcomes research other surveillance markers would enhance consortium is one step that could be taken to the ability to care for patients with small promote standardization. intestinal disorders, including SBS and intestinal failure, as well as recipients of intestinal transplants.

Intestinal Failure and Regeneration, Nutritional Disorders and Support, Surgically Modified Gut, and Transplantation 115 Low (A) and high (B) power microscopic views of the esophageal epithelium in eosinophilic esophagitis, showing distinctive features of this condition, such as increased numbers of immune cells called eosinophils.

Image courtesy of Dr. Glenn Furuta. Reprinted from Gastroenterology, 133, Furuta GT, Liacouras CA, Collins MH, Gupta SK, Justinich C, Putnam PE, Bonis P, Hassall E, Straumann A, Rothenberg ME. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment, pp. 1342-1363, Copyright 2007, with permission from Elsevier.

 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Diseases of the Oropharynx and Esophagus

SUMMARY OF RESEARCH GOALS

Because normal functioning of the oropharynx and esophagus can be compromised by a wide spectrum of diseases, the Commission suggests a number of research goals that address the diverse etiologies and potential treatments for these disorders. Research to understand the neuromuscular biology of the oropharynx and esophagus is critical to developing therapies for conditions like swallowing disorders brought on by stroke, premature birth, non-erosive reflux disease (NERD), and other motility disorders that affect this portion of the gastrointestinal (GI) tract. Similarly, more studies are needed to identify better therapeutic targets for gastroesophageal reflux disease (GERD), among the most common diagnoses for a digestive disorder in the U.S. GERD is also associated with increased risk for Barrett’s esophagus and esophageal cancer. Thus, research is needed to uncover the risk factors and mechanisms of disease progression in order to develop more effective prevention and treatment strategies. The emergence of eosinophilic esophagitis and other inflammatory diseases of theesophagus over the last decade highlights the need for research to define the clinical course of these poorly understood diseases and design rational therapies to reverse them. Progress toward these research goals will help to reduce the significant economic toll that these diseases, particularlyGERD, take on individuals and the U.S. healthcare system.

Diseases of the Oropharynx and Esophagus 117 INTRODUCTION AND BACKGROUND The oropharyngeal musculature is striated, signifying its close control by . The oropharynx and the esophagus can be This pattern continues for the proximal one- considered the gateways to the GI tract and, third of the esophagus, after which it is replaced as such, are critical for the digestive processes by smooth muscle, which is more characteristic that follow. Although the two components of of the rest of the GI tract and indicative of the the oropharynx (i.e., mouth and ) are greater influence of the intrinsic nerve cells relatively distinct anatomically, the oropharynx found in the wall itself (i.e., the enteric nervous is usually considered as a unitary functional system). Despite its deceptively simple tubular entity from a gastroenterological perspective, form, the esophagus is in fact a complex organ. with its overarching purpose being to facilitate Like much of the GI tract, it is organized safe passage of the ingested of food cross-sectionally into several concentric layers: across the opening to the airways and into the epithelium (which is squamous in nature, the esophagus proper. In accordance with this similar to the skin), the submucosa, and two function, this region is under tight control of principal muscle layers, with the myenteric the central nervous system (CNS); its nerves plexus sandwiched in between. In addition, it and muscles are, therefore, its most critical receives extensive innervation from the vagal components, with even subtle dysfunction (cranial) and spinal nerves. Any one of these resulting in considerable morbidity. It is not components or layers can be the primary or surprising, therefore, that cerebrovascular secondary site of a variety of diseases. accidents (strokes) and subsequent uncoordinated nerve activity account for the The heterogeneous nature of these organs vast majority of functional disturbances in this makes them vulnerable to a considerable region, with only a minority related to other variety of pathologic processes and a structural lesions. This is a huge problem: correspondingly broad clinical spectrum nearly 700,000 strokes per year occur in the that affects patients across all demographic U.S. alone, with the incidence of post-stroke categories. This chapter focuses on some dysphagia (difficulty inswallowing) ranging of the diseases in these organs that have from 37-45 percent, even with cursory screening large impacts, as defined either by their techniques, and as high as 64-78 percent with socioeconomic effects or by the burden of formal instrumental testing. Dysphagia not only suffering they impose on individual patients. leads to impairment in food intake, but also Perhaps the most well-known and most puts these patients at a 3-fold or higher risk common of these syndromes is GERD, for pneumonia. Disturbances in oropharyngeal commonly referred to as “heartburn.” GERD function are also common in the elderly, is common worldwide, but is particularly perhaps independently of overt lesions in the prevalent in developed countries. The CNS. Swallowing disorders have been reported prevalence of heartburn (with or without acid in 30-40 percent of nursing home residents and regurgitation) at least once a week ranged 6.9 percent of the surveyed general population. from 14-29 percent in the U.S. population The importance of an abnormal swallowing and did not differ between Blacks and Whites mechanism in the elderly is reflected by the in a survey from Houston. In a 2004 report, high incidence of aspiration pneumonia in GERD was the leading physician diagnosis autopsy studies. A majority of patients with for GI disorders, accounting for almost 7 swallowing dysfunction will, therefore, require million outpatient visits. This imposes rehabilitation therapy. a severe economic cost, estimated to be over $11 billion in 2004. Much of this cost is related

118 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases to medications, particularly proton pump conditions, such as achalasia with an incidence inhibitors (PPIs), for which nearly 8 million of approximately 1 in 100,000 per year, which prescriptions were written per month in are nevertheless important because of their 2004—a number that represents more than chronic and lifelong nature. Other disorders a doubling compared to the previous 5 years. may perhaps be more common, but are less Beyond economic considerations, the most well defined clinically and pathophysiologically. sinister health threat represented by GERD In addition, severe GERD is often associated is the elevated risk for adenocarcinoma of with significant motility abnormalities of the the esophagus. The incidence of esophageal esophagus, either as a cause or effect, and adenocarcinoma has grown dramatically in these may lead to symptoms by themselves in recent years, and many experts link it to the some patients. Abnormal esophageal motility rise in GERD in the general population. This is a consequence of some systemic disorders, is based on the current paradigm that chronic notably diabetes and scleroderma or related GERD leads to Barrett’s esophagus, a change connective tissue syndromes. Particularly in the epithelial lining of the esophagus from in the latter, an incompetent sphincter and a squamous to an intestinal type. In some impaired esophageal acid clearance can lead to patients, such a change is associated with devastating reflux with serious consequences, dysplasia, an abnormality in the appearance of such as stricture formation. the lining cells that indicates their instability and tendency to progress to cancer, which Neural changes can not only produce motility occurs in about 0.5 percent of cases per year. disturbances in the esophagus, but can also lead Disorders affecting other parts of the body to sensory abnormalities and a hypersensitive have also been ascribed to GERD, including esophagus that may account for a significant asthma, dental problems, and , nose, and number of patients with non-cardiac chest throat disturbances (e.g., erosions, laryngitis, pain. This syndrome probably results from hoarseness, and even laryngeal cancer), but in multiple etiologies with prominent psychosocial many cases actual causality has been difficult components, akin to what has been described to establish. for other painful functional GI disorders, such as functional dyspepsia and irritable bowel Another common form of esophageal cancer syndrome. “Chest pain, not otherwise specified” is squamous cell cancer, which arises at a is the most common inpatient GI diagnosis, location higher up in the esophagus and with over 320,000 hospital discharges in a is strongly associated with smoking and recent year. alcohol intake. GERD does not appear to be a risk factor for this cancer. Unlike Barrett’s Esophageal diseases affect children as well esophagus, which is predominantly a disease as adults. “Reflux” is extremely common of white males, squamous cell cancer affects in neonates and can assume pathologic African Americans disproportionately, with proportions requiring treatment in a subset of an incidence that is several times greater, infants. Such children are more likely to have although the incidence appears to be declining. GERD when they grow up. However, there is a paucity of good data on effective treatment Another major class of disorders that affects in this age group. Swallowing dysfunction the esophagus arises from disturbances of resulting in oral aversion, dysphagia, and motility—the coordinated action of nerves and regurgitation are also very common problems muscles that produces effective propulsion. in neonatal and pediatric intensive care These disorders include relatively rare units, often associated with prematurity

Diseases of the Oropharynx and Esophagus 119 and oral/pharyngeal trauma from medical in renewed interest in devising rehabilitative devices such as endotracheal and feeding approaches to swallowing disorders. Such tubes. Currently, inadequate information an approach would benefit an overwhelming is available on the normal development majority of patients with swallowing disorders. of swallowing function, the mechanisms The availability of functional imaging should responsible for its perturbation, and effective provide a powerful tool for manipulation of means to prevent and treat the same. Finally, brain centers involved in swallowing to either a recently described syndrome, eosinophilic induce or speed recovery. esophagitis, has been increasingly recognized in both children and adults. This condition is Gastroesophageal reflux disease characterized by esophageal inflammation and infiltration by eosinophils, which are white Considerable insight has been obtained into blood cells that typically are associated with the pathways of acid-induced injury to the allergies and some infections. Symptoms of esophagus. Luminal acid and initially eosinophilic esophagitis include vomiting, damage the esophageal epithelium by attacking abdominal pain, poor growth, difficulty with the apical junctional complex (APJ), a group of swallowing, and food impaction. This condition structures that control the permeability of ions is often misdiagnosed as GERD. Although the and aqueous molecules passing through the underlying etiology of eosinophilic esophagitis intercellular space. The consequence of this is is often unidentified, foodborne and airborne a “leaky” epithelium with dilated intercellular allergens have been frequently implicated. spaces, the latter a clinically identifiable Currently, effective treatments are limited to hallmark of early acid injury to the tissue. In steroids and diet restriction. turn, protons and other noxious factors (e.g., pepsin) gain access to subepithelial structures, Finally, a variety of infections can afflict the such as nerves and muscle, with several esophagus, with the most common being fungal potential consequences. Neural stimulation (e.g., candida) or viral (e.g., cytomegalovirus may result in initiation and/or amplification or virus); these are typically of inflammation and generate symptoms seen in patients with compromised immune of heartburn and chest pain. An attractive systems, such as those with HIV-AIDS. With candidate for mediating these effects of protons modern therapeutic regimens, such cases are is the vanilloid receptor, TRPV1, which is becoming less common. expressed by nociceptive neurons and responds to noxious stimuli, such as acid and heat. Acute, acid-induced esophagitis is reduced in animals RECENT RESEARCH ADVANCES lacking TRPV1, suggesting that refluxed acid may induce inflammation through TRPV1, Oropharyngeal physiology and possibly via neurogenic mechanisms. Muscle- pathophysiology produced inflammatory products may also cause dysfunction; for example, in esophageal A major advance has been the systematic circular muscle, production of cytokines, evaluation of the biomechanical aspects of hydrogen peroxide, -activating factor, swallowing function. In addition, recent studies and prostaglandin E2 results in inhibition of have addressed the effect of bolus volume, acetylcholine release from cholinergic motor consistency, and temperature on the swallowing neurons without affecting the integrity of the apparatus. A better understanding of the contractile mechanisms. biomechanical aspect of swallowing has resulted

120 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Thus, in addition to epithelial injury and trials, on the safety and efficacy of emerging symptom generation, acid reflux can alter endoscopic, anti-reflux procedures, as well esophageal neuromuscular function in several as surgical procedures, such as prosthetic ways, perpetuating the process by decreasing reinforcement of the hiatus in the repair of lower esophageal sphincter (LES) tone and giant hiatal . impairing peristalsis and acid clearance. Further, esophageal longitudinal smooth Barrett’s esophagus muscle function may also be affected and can contribute to both reflux and delayed clearance Barrett’s esophagus can be reversed in some, by creating a spatial separation of the LES but not all, patients with endoscopic treatments and diaphragm. From the perspective of the that either ablate or mucosally resect the mechanics of the esophagogastric junction epithelium. The neosquamous epithelium (EGJ), axial motion attributable to longitudinal may have less malignant potential than the is key to the normal Barrett’s-affected tissue it replaces. The ability opening mechanism, and disordered EGJ to effect reversion in the mucosa suggests mobility and compliance may play a role in the that there is an underlying “stem” cell, which pathogenesis of reflux. Prolonged contraction can either revert to the normal pathway of this may also contribute to of differentiation to a stratified squamous generation of symptoms. epithelium or continue to differentiate down the specialized intestinal metaplastic pathway. Another advance in this area has been Continued development of these treatments the elucidation of the neurophysiology could result in the ability to prevent the and neuropharmacology of transient LES progression of Barrett’s esophagus to cancer relaxations, a major mechanism of reflux. This and may improve healthcare utilization by has raised the prospect of mechanistically decreasing expenditures on surveillance directed therapy using agents such as endoscopy. the GABAB agonist baclofen in treating symptomatic reflux. Changes in gene expression likely precede the development of histologic Barrett’s esophagus. Progress has also been made in understanding For instance, the expression of a homeobox and managing childhood GERD, symptoms of gene, CDX2, in esophageal epithelium leads which are reported in 8.2 percent of children to metaplasia and may be an early marker for ages 10-17 years. As in adults, a variety of non- Barrett’s esophagus. Also, epigenetic alterations esophageal symptoms have been associated may be instrumental in the development of with childhood GERD, including asthma, malignancy. Hypermethylation of the promoter hoarseness, , , and otitis media regions of various tumor suppressor genes are (ear infection). Natural history studies show associated with increasing degrees of dysplasia. that while symptoms improve, histopathology may remain abnormal. Initial studies show The demographic, anthropometric, and an excellent safety profile forPPI use in symptom-based risk factors for Barrett’s children, although infectious gastroenteritis esophagus have been better elucidated. and pneumonia may be more common among Despite reports of the association of Barrett’s children using PPIs. esophagus with chronic heartburn symptoms, data suggest that Barrett’s esophagus is Finally, there has been significant clinical relatively common regardless of whether a research, including randomized, controlled patient has a history of heartburn. In fact,

Diseases of the Oropharynx and Esophagus 121 a substantial proportion of patients with with eosinophilic esophagitis. In 2006, a novel adenocarcinoma of the esophagus have no prior translational study identified the key role of symptoms of heartburn. Obesity appears to eotaxin-3 in eosinophilic esophagitis. Utilizing be a risk factor for Barrett’s esophagus and, a combination of microarray techniques, in for any given body mass index, subjects with vivo and in vitro studies, eotaxin-3 was shown visceral adiposity may be at higher risk than to be significantly up-regulated compared to those with higher hip to waist ratios. Multiple controls. Further studies showed mutation trophic hormones are elevated in subjects of this gene in affected patients, and basic with central adiposity, which may explain the analysis confirmed a significant role in this increased risk of metaplasia in this group. inflammatory process. In addition to potential Preliminary data have been reported showing molecular targets for treatment, these data the influence of heritability on the development add to the growing body of knowledge of the of Barrett’s esophagus. central role of the esophageal epithelium in generation of the inflammatory/allergic cascade A number of novel, high-resolution imaging that ultimately translates into the clinical techniques show promise in identifying high- manifestations of the disease. grade dysplasia and early cancers in Barrett’s esophagus patients with moderate sensitivity Esophageal motility and “functional” and specificity. To date, these “optical biopsy” disorders methods do not demonstrate the ability to survey large areas of Barrett’s esophagus. The pathophysiology of achalasia has been reasonably well characterized and appears Eosinophilic esophagitis to result from a relatively selective loss of nitrergic (inhibitory) neurons supplying the Eosinophilic esophagitis is an immune- muscle of the LES. However, the etiology of mediated inflammatory disorder that is often this process remains unknown, although there triggered in atopic individuals by food products is growing evidence for a possible autoimmune or inhaled allergens. It is characterized by process associated with antibodies directed infiltration of the esophageal wall, including against neuronal elements. There have been the epithelium, with mast cells and eosinophils. some advances in the treatment of this Clinically, the inflammatory response by mast disorder. Botulinum toxin injections have been cells and eosinophils within the esophagus shown to be effective in relieving symptoms results in symptoms of chest pain, heartburn, in this condition and, although the benefit and dysphagia—the latter due either to is short-lived, they are valuable alternatives peristaltic dysfunction or to mechanical in patients who are not fit for more invasive narrowing of the lumen by a dense fibrotic forms of therapy. Pneumatic dilation has been reaction within the wall. Notably, infiltration of shown to be of limited efficacy in younger the esophagus by eosinophils has been shown patients, in whom laparoscopic myotomy to result from the release of eotaxin-3 and IL-4, appears to be the best option. This surgical IL-5, and IL-13 by squamous epithelial cells. approach results in less morbidity and earlier This observation provides molecular targets post-operative recovery than traditional, open for potential treatments for the condition. For myotomy. The demonstration that neural stem instance, intravenous antibodies to IL-5 can cells can be injected into the GI tract and reduce both blood and esophageal eosinophilia result in recovery of nitrergic function raises and improve the quality of life in patients hope for a true cure for this condition.

122 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases The recognition of esophageal hypersensitivity pathophysiologic events that lead to esophageal and, in particular, emerging concepts of post- symptom generation in patients. This includes inflammatory neuronal sensitization have been non-cardiac chest pain and “emerging” important in understanding the spectrum of syndromes, such as NERD.

14 Goals for Research 14

Research Goal 7.1: Understand the ß Conduct clinical studies of recovery and neurobiology of oropharyngeal structure and plasticity with creative use of functional imaging function in health and disease. and novel interventional techniques. ß Understand physiologic and pathologic Identifying novel molecular, physiologic, and communication between the functional anatomic targets within the oropharynx will components of the aerodigestive tract. accelerate the development of more effective ß Understand the effects of gastroesophageal reflux treatments and/or functional rehabilitation of on the airways, including the and bronchi. stroke-induced swallowing dysfunction, a major ß Define the effects of sleep abnormalities on cause of morbidity, particularly in the elderly. upper GI tract physiology. Similarly, understanding the processes involved in the development of swallowing function and the mechanisms by which these processes Research Goal 7.2: Understand the clinico- are disturbed in the neonate is very important. pathologic mechanisms leading to and/or Currently, our approach to these problems is associated with GERD and identify novel empirical and palliative at best, with little ability to molecular, physiologic, and anatomic targets for prevent permanent disability. more effective and rational treatment.

In addition, this region is vulnerable to the effects Although effective in the majority of patients, acid of gastroesophageal reflux with consequences suppression is an indirect method for the treatment that potentially affect the airways in the form of of GERD and its complications. Further, treatment laryngitis and asthma. Much needs to be learned is indefinite in duration because of the chronic about the pathogenesis and treatment of these nature of the disorder. Developing more effective problems. treatments, whether they are pharmacological, endoscopic, or surgical in nature, requires a better Objectives: understanding of the underlying mechanisms. ß Develop useful animal models of oropharyngeal swallowing disorders to facilitate neuropathologic Objectives: studies of central and peripheral components and ß Understand the clinical spectrum, outcomes, evaluate the effects of interventions directed at and natural history of childhood reflux and its specific molecular and/or cellular targets. relationship/evolution into adult patterns of disease.

14 Research Goals are numbered for ease of reference only; the numbers do not indicate prioritization of scientific topics.

Diseases of the Oropharynx and Esophagus 123 Goaloalss for for Rese Rarcesearchh

ß Validate and develop more effective and/or less Research Goal 7.4: Understand the invasive long-term approaches to GERD and epidemiology, natural history, and outcomes of identify more precisely the clinical, anatomic, eosinophilic esophagitis and identify targets for and/or functional predictors of response. more rational and effective therapy. ß Understand the biologic basis of gastroesophageal reflux, hiatalhernia, and Eosinophilic esophagitis is rapidly emerging as a GERD-associated esophageal dysmotility, significant health problem in children and adults. including the role of biomechanical factors and Since it has only been formally recognized in the longitudinal muscle. last decade or so, very little is known about this disease, and much research is needed to answer fundamental questions relating to clinical course Research Goal 7.3: Define the mechanisms and treatment. responsible for esophageal injury and repair, with particular emphasis on the interactions among Objectives: components of the esophageal wall. ß Determine risk factors, natural history, and outcomes of patients with eosinophilic Acute and chronic inflammation of theesophagus esophagitis and identify biomarkers for disease can lead to serious complications, such as strictures, activity and progression. dysmotility, and pre-malignant or malignant ß Identify novel targets and interventions for more transformation. Esophagitis results from a complex effective and rational therapeutic approaches to interaction between the inciting factor and the eosinophilic esophagitis and other inflammatory tissue response, which involves many diverse disorders of the esophagus. cell types, some of which are harmful and others perhaps beneficial. A full understanding of these pathways will pave the way for more effective Research Goal 7.5: Understand the methods for treatment and prevention of many etiopathogenesis of Barrett’s esophagus, determine esophageal disorders. risk factors associated with its progression, and identify novel targets and/or therapies for Objectives: chemoprevention and treatment. ß Elucidate mechanisms of increased permeability in the esophageal epithelium. Despite several decades of research on Barrett’s ß Understand the role of neural and muscular esophagus, this disorder continues to be a major elements in modulation or enhancement of clinical challenge. Although it is strongly associated esophageal injury. with GERD, little is known about the biologic ß Characterize acute and chronic mechanisms mechanisms by which chronic reflux leads to responsible for esophageal epithelial squamous transformation of the esophageal lining or the cell repair. particular genetic or acquired factors that predispose ß Determine the role of foodborne, airborne, and a given patient with reflux to this complication. other environmental allergens in promoting eosinophilic esophagitis and the underlying Objectives: mechanisms. ß Understand the initiation of Barrett’s esophagus, ß Define basic pathogenic mechanisms by which with particular emphasis on identifying the eosinophils mediate esophageal dysfunction. putative stem cell involved and studying its biology.

124 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases GOALS FOR RESEARCH

ß Define the contribution and etiopathogenic role of esophageal dysfunction remain largely unknown, environmental (e.g., smoking) and genetic/familial leading to therapies that are generally ineffective factors in the development of Barrett’s esophagus. and palliative at best. Similarly, although chest ß Develop biomarkers that reliably predict dysplastic pain or discomfort of putative esophageal origin and neoplastic progression. is a major drain on healthcare resources, little ß Identify novel molecular targets for is known about its underlying neurobiology or pharmacological approaches to restoring a potential targets for treatment. stable epithelial phenotype in patients with Barrett’s esophagus. Objectives: ß Conduct chemoprevention studies in subjects with ß Understand the neurobiology of normal Barrett’s based on molecular pathways identified and abnormal esophageal sensation and through ongoing studies on human tissue and identify novel molecular targets for more animal models. effective and rational treatment of esophageal ß Develop better and more cost-effective tools for hypersensitivity associated with disorders such screening and surveillance. as non-cardiac chest pain and NERD. ß Understand the etiopathogenesis, genetic predisposition, and risk factors for esophageal Research Goal 7.6: Understand the etiology motility and functional disorders, including the and biology of esophageal neuromuscular function roles of autoimmunity, environmental factors (e.g., in health and disease and develop more effective viruses), relationship to GERD, genetic factors, and treatments. molecular candidates (e.g., ALADIN). ß Identify novel therapeutic targets for Esophageal dysmotility can be primary in origin pharmacological, cellular (e.g., stem cell or result from several systemic diseases, such as treatment), and physical (e.g., endoscopic) diabetes or connective tissue disorders. In most approaches for more effective and rational cases, the pathologic mechanisms responsible for treatment for esophageal motility disorders.

MAJOR CHALLENGES AND STEPS diagnostic criteria, the lack of generally TO ACHIEVE the RESEARCH GOALS available and reliable methods for physiologic testing, and the inaccessibility of tissue for Animal models: Many, if not most, disorders histopathologic correlation. Further, because of the oropharynx and esophagus lack complete of variations in practice management, a true understanding in terms of the underlying patho- epidemiological and clinical picture of these biology. This is true even of common problems, disorders has been difficult to obtain. Such such as GERD, and is due in part to a lack of information is necessary for planning studies convenient and valid experimental models. to elucidate pathogenic mechanisms and improve on current therapeutic strategies. Standards for diagnosis: Challenges in less common or emerging disorders, such as Interdisciplinary research: A major challenge esophageal dysmotility syndromes, eosinophilic affecting some disorders in this group is the lack esophagitis, and even Barrett’s esophagus, of cross-fertilization among disciplines. This include the small number of patients seen issue is best exemplified byswallowing disorders by any one center, the absence of uniform secondary to CNS pathology, an area that seems

Diseases of the Oropharynx and Esophagus 125 to have “fallen through the cracks” between the National research resources: The neuroscience and GI specialties. In contrast to establishment of multicenter consortia with other areas of CNS, research progress in the the ability to build large databases and patient neurobiology and pathology of the “swallowing registries would promote progress in several center” and related structures has lagged. ways. Such resources would enable researchers Similarly, although emerging disorders, such to make a population-based determination of as eosinophilic esophagitis, initially present the incidence of these disorders, their etiologies, to gastroenterologists, research progress in and risk factors. Researchers could also analyze understanding these conditions may require the the natural history of disease, including timing scientific input of specialists in immunology of onset, progression, prognosis, quality of life, and allergy. cost, and healthcare utilization, and collect annotated tissue and serum specimens to study Disease definitions: In diseases like Barrett’s molecular and cellular mechanisms, as well esophagus, enormous variability in disease as to illuminate genetic and environmental definitions and histologic grading can be found influences. Collaborative trial groups that bring in the literature. Even among expert centers, together experts from relevant disciplines (e.g., one group’s low-grade dysplasia is another’s immunology, oncology, and surgery) would non-dysplastic disease. A multinational be able to validate clinical protocols for the consensus conference to arrive at standardized diagnosis and management of these patients disease definitions would strengthen the field. and conduct trials of chemopreventive and therapeutic strategies. Multicenter studies Validation of novel interventions: Another could be more effective than single-site trials, barrier to the advancement of knowledge in which are often restricted by insufficient this area is that novel imaging and therapeutic patient numbers. techniques are disseminated prior to rigorous, multicenter testing by conflict-free groups. Advanced technology: Much progress in The result is that multiple “infant” strategies this area could be made through technological are being developed, with no effort to grade breakthroughs, and such research and the relative value of the interventions, leading development efforts should be actively to wasted effort and unnecessary costs, as encouraged. Examples include endoscopic access well as suboptimal patient outcomes. Direct for obtaining tissue samples from deeper layers marketing to community gastroenterologists of the esophagus, better physiologic tests, and and surgeons is occurring before rigorous less invasive and more effective anatomic and testing. Emphasizing rigorous testing of physiologic approaches to treatment. Although this technology as part of a Request for there is significant overlap between esophageal Applications may improve this situation. motility disorders and their counterparts in Finally, in this context, it is important to point the rest of the GI tract, the esophagus, because out that past attempts at limiting cancer in of its limited length and easy access, can be the setting of Barrett’s esophagus have focused viewed as a model to test hypotheses of a more on subjects with chronic GERD symptoms. general nature. An example would include the Increasing evidence suggests that such an phenomenon of visceral hypersensitivity, the approach is, at best, incomplete and flawed study of which has best been conducted in the and, at worst, largely ineffective and esophagus. Similarly, if a stem cell approach will cost-inefficient. work at all, it is best tested in the esophagus, which offers a relatively easy site for local (endoscopic) delivery.

126 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Diseases of the Oropharynx and Esophagus 127 Helicobacter pylori adhering to the surface of the . H. pylori are a major cause of peptic ulcer disease.

Image courtesy of Eye of Science/Photo Researchers, Inc.

 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Diseases of the Stomach and Small Intestine

SUMMARY OF RESEARCH GOALS

The impact of research on diseases of the stomach and small intestine is epitomized by the discovery of Helicobacter pylori and its role in peptic ulcers, which quickly revolutionized the treatment of many, though not all, patients with peptic ulcers. To capitalize on this and other advances, the Commission proposes several research goals to improve understanding of the diverse diseases that affect the stomach and small intestine and to accelerate development of effective therapies. Peptic ulcer disease (PUD) can be triggered by multiple causes in addition to H. pylori. Research efforts are needed to understand the mechanisms of ulcer formation and mucosal injury and to develop new approaches to prevention and treatment of ulcers, especially those associated with non-steroidal anti-inflammatory drugs (NSAIDs).

Developing effective treatments for diarrhea and other maldigestive/malabsorptive diseases requires better understanding of the fundamental mechanisms of water, nutrient, and electrolyte transport in the intestine. Research on celiac disease and other autoimmune and allergic diseases that affect the digestive tract is needed to uncover the genetic and environmental triggers of such conditions and to improve methods of diagnosis and treatment. Finally, focused research efforts are critical for diseases of unknown origin, such as necrotizing enterocolitis (NEC) and eosinophilic gastrointestinal (GI) diseases, for which few effective treatment options are available.

Diseases of the Stomach and Small Intestine 129 INTRODUCTION AND BACKGROUND (e.g., dyspepsia). The proportion of ulcers due to NSAID use is beginning to approach that caused Diseases of the stomach and small bowel are by H. pylori. NSAIDs are the most commonly common and cause significant morbidity, used medication in the U.S., with regular use by economic hardships, and health consequences. 11 percent of the population and intermittent Acid-peptic ulcer diseases alone accounted for use by a much greater number of individuals. an estimated $2.8 billion in direct costs in 2004. For this reason, the GI effects of NSAIDs incur a Diarrheal diseases, which are major causes tremendous healthcare burden that is expected of morbidity and mortality on a global scale, to rise as the population ages and the prevalence cost the American public close to $3.0 billion in of arthritis increases. The Zollinger-Ellison 1998, notwithstanding the huge indirect costs syndrome (ZES) is caused by a associated with lost wages and work produc- (tumor of -secreting G cells), which tivity. Celiac disease, an immune-mediated leads to excessive production of the hormone disorder that primarily affects the GI tract, gastrin, resulting in gastric hyperacidity. ZES had been considered a rare disease. However, may present with severe or refractory peptic recent studies suggest that it affects as many ulceration, ulcers in unusual sites, ulcer compli- as 3 million Americans (roughly 1 percent of cations, severe esophagitis, and/or unexplained the population), indicating that the disease is diarrhea. Other peptic diseases include stress widely unrecognized across the country. NEC, an ulcers in critically ill patients, viral diseases inflammatory condition of the distalsmall bowel in immunocompromised or post-transplant and colon leading to bowel necrosis, perforation, patients, ulcerations associated with cocaine and and death, affects approximately 7 percent of mesenteric ischemia, and inflammatory bowel premature infants weighing less than 1,500 diseases (IBD). Although less common, these grams; about one-quarter of those infants will diseases are often difficult to manage and are, succumb to the disease. therefore, inadequately treated.

Gastroduodenal disease: PUD has a lifetime Two paradigm-shifting advances in the prevalence of approximately 12 percent in men understanding and treatment of gastroduodenal and 9 percent in women. A major cause of PUD, disease—the discovery of H2 receptor Helicobacter pylori colonizes the stomachs of blockers that could be used to treat peptic ulcers at least half of the world’s population and is a (among other conditions) without surgery and strong risk factor for gastric cancer. Successful the discovery of H. pylori and its causative role treatment of H. pylori virtually eliminates the in PUD—were recognized by the award of Nobel subsequent risk of developing PUD in response Prizes in Physiology or Medicine, in 1988 and to this microbial pathogen. Patients may have 2005 respectively. ulcers that recur frequently, ulcers that require large doses of medication for healing, or H. Diarrheal and malabsorptive/maldigestive pylori-negative duodenal ulcers that occur in diseases: Acute diarrheal diseases are the absence of NSAIDs. These drugs, which are primarily caused by food or infectious agents commonly used for prevention of cardiovascular and, in most cases, are self-limiting. Medical events and pain, are another important cause of intervention is usually not necessary except in PUD. GI side effects, which are the main factor the very young or elderly. Infectious diarrheal limiting the use of NSAIDs, include life- diseases on a worldwide basis cause over 2.5 threatening upper GI complications (e.g., million deaths per year, particularly in children bleeding, perforation, or obstruction), uncompli- in the first year of life. In 40 percent of cases of cated symptomatic PUD, and other symptoms chronic diarrheal diseases (lasting more than

130 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases 2 weeks), the cause cannot be identified and ) and autoimmune diseases during patients are often chronically dehydrated. No late childhood and adulthood due to inadequate effective anti-diarrheal agents are available development of the mucosal immune system to treat severe or chronic diarrheal diseases. (e.g., lack of oral tolerance). Research suggests Similarly, there is an inadequate under- that early interaction of colonizing bacteria with standing and treatment of malabsorptive and the neonatal gut can orchestrate development maldigestive disorders, many of which cause of the mucosal immune system. The incidence chronic diarrhea, malnutrition, and metabolic of autoimmune diseases has increased substan- abnormalities. tially during the last few decades.

Autoimmune and allergic diseases of the Necrotizing enterocolitis: NEC puts affected bowel: Celiac disease is an immune-mediated infants at risk for intestinal morbidity and poor disorder that primarily affects the GI tract of neurodevelopmental outcome. The primary genetically predisposed individuals. The disease risk factors for NEC appear to be prematurity, is caused by an aberrant immune reaction to bacterial colonization, altered vascular gliadin, a gluten protein of dietary grains. It is regulation, and enteral feeding. Since these characterized by chronic inflammation of the issues are common to all premature infants, it small intestinal mucosa that results in atrophy is currently impossible to predict which infants of intestinal villi, malabsorption, and a variety will develop this devastating disease. Mucosal of clinical manifestations, including diarrhea, injury is believed to be caused by a breach in the abdominal cramping, pain, and distention. intestinal mucosal barrier, leading to bacterial Untreated celiac disease may lead to vitamin translocation and activation of an inflam- and mineral deficiencies, osteoporosis, and other matory cascade. There is also evidence of an extraintestinal problems. While there is no exaggerated immune/inflammatory response to cure, considerable progress has been made in pro-inflammatory stimuli. No specific treatment understanding celiac disease and in preventing is available, and supportive measures are often or curing its manifestations by dietary interven- inadequate because of the rapid progression of tions. The strong genetic predisposition to NEC after diagnosis. Despite many advances in celiac disease is attributed mainly to genetic the care of premature infants, the incidence of markers, known as HLA-DQ2 and HLA-DQ8, NEC has remained remarkably constant over that are present in affected individuals. Glutens the past 4 decades. found in wheat, barley, and rye interact with these HLA molecules to activate an abnormal Eosinophilic gastrointestinal disorders mucosal immune response that is necessary, (EGIDs): EGID, originally thought to be a rare but not sufficient, to induce tissue damage. condition, has been diagnosed with increasing Innate immune activation is required to induce frequency over the last decade. Clinical activation of intraepithelial lymphocytes, which manifestations include vomiting, abdominal consequently mediate tissue damage. pain, malabsorption, GI obstruction, and . The cause is unknown, but the disease Inadequate colonization of the newborn gut has been associated with allergic symptoms. with commensal bacteria or a lack of exposure The diagnosis of eosinophilic gastroenteritis to neonatal infectious agents may result in an requires a histologic demonstration of markedly increased expression of allergic conditions (e.g., increased numbers of eosinophils in the GI tract.

Diseases of the Stomach and Small Intestine 131 RECENT RESEARCH ADVANCES Cyclooxygenases in the pathogenesis of peptic diseases associated with NSAIDs Helicobacter pylori infection and resulting peptic diseases The identification of the role that cyclooxy- genases (COX-1, COX-2) play in regulating Eradication of H. pylori significantly decreases NSAID-induced GI injury led to the devel- peptic ulcer risk and likely reduces gastric opment of agents that selectively inhibit cancer risk in infected individuals without specific pathways (e.g., COX-2) in order to pre-malignant lesions. However, only a small reduce GI toxicities associated with the use of percentage of colonized persons ever develops traditional non-selective NSAIDs. Although symptomatic disease. The identification of COX-2 inhibitors can reduce side effects in certain host and H. pylori genotypes that the GI tract, studies have demonstrated an synergistically augment the risk for gastric increase in cardiovascular morbidity and cancer was an important step that may permit mortality associated with these agents. This to focus diagnostic and eradication has reinforced the strategy of combining a strategies in high-risk populations to reduce potent acid-suppressing agent with NSAIDs in the risk of pathologic outcomes. high-risk patients to prevent ulcer bleeding.

Bone marrow-derived stem cells and Gene defects in diarrheal, malabsorptive, formation of gastric tumors associated and maldigestive diseases with chronic mucosal inflammation The major proteins that participate in Circulating bone marrow-derived stem cells transport across the intestinal epithelium of may contribute to the formation of gastric several nutrients (e.g., sodium, potassium, tumors within H. pylori-inflamed mouse chloride, D-glucose, L-, and heavy gastric mucosa. This concept has opened up metals) have been identified. Some diarrheal, new avenues for exploring the pathogenesis malabsorptive, and maldigestive diseases of microbially induced gastric cancer, as well are now understood to result from genetic as other malignancies that arise within the mutations in these proteins. These diseases context of chronic inflammation. include D-glucose/D- malabsorption, congenital chloridorrhea, congenital sodium Pathogenesis of Zollinger-Ellison syndrome diarrhea, Menke’s disease, and congenital deficiency. Progress has been made Key research advances in ZES are the in understanding how these proteins work in identification of theMEN 1 gene product cell, experimental, and some animal intestinal menin, the finding that this protein interacts epithelial models. with numerous transcription factors, and the generation of mouse models of MEN 1. This Intestinal regulatory systems, such as basic research characterizing the MEN 1 gene enteroendocrine cells, in intestinal complements recent studies demonstrating that digestion and absorption ZES within the context of MEN 1 is frequently due to multifocal duodenal with Malabsorption can result from defects or abnor- mutations in specific menin domains. These malities in integration of intestinal functions. tumors are difficult to localize and remove, For instance, children with a mutation in and such patients tend to be more refractory to neurogenin-3, an intestinal transcription factor, treating the consequences of hypergastrinemia fail to develop enteroendocrine cells, which and hyperacidity. are believed to be essential for paracrine and

132 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases juxtacrine regulation of mucosal function. proteins, and permeability of the paracellular As a consequence, congenital malabsorption pathway. In addition, changes or defects in plus diarrhea results even when a fat-free tight junctions are important mechanisms that diet consisting of oral rehydration solution can underlie or contribute to microbial patho- is consumed. Thus, integration of digestive genesis and mucosal inflammation (e.g.,IBD). and absorptive functions is a critical aspect of normal physiology. Pathogenesis and management of celiac disease The intestinal microflora in health and disease Intestinal intraepithelial lymphocytes, IL-15, and natural killer receptors have been New technologies to study the normal recognized as key mediators of the effector human intestinal microflora have revealed phase of celiac disease and the development the complexity and diversity of the enteric of . This finding suggests that microflora, many species of which cannot be therapies designed to block specific innate cultivated by standard techniques. These immune responses can be developed to treat advances are redefining our understanding of celiac disease. how luminal bacteria contribute to bacterial overgrowth, intestinal malabsorption or Because the human intestinal tract is deficient maldigestion, mucosal inflammation, and in the secretion of prolyl endopeptidases, diarrheal diseases. New research suggests digestion of dietary gluten in the small intestine that alterations in composition of the human is incomplete. As a consequence, relatively large microflora have a role inobesity. proline-rich gluten peptides are generated that can uniquely bind to the HLA-DQ2 and Improved oral rehydration solutions HLA-DQ8 major histocompatibility proteins with subsequent activation of immune mecha- Oral rehydration solutions (ORS) have been nisms leading to tissue damage. Thus, strategies used effectively to treat acute and infectious to supplement diet with enzymes that can fully diarrheal diseases, reducing deaths from acute digest these large gluten peptides are being diarrhea worldwide from 12 million to less than developed as a useful adjunct to the gluten-free 2 million per year. In the past several years, the diet in the treatment of celiac disease. effectiveness and patient acceptability of ORS have been improved by lowering the osmolarity Many gluten peptides can activate celiac of ORS. Adding poorly hydrolyzable (e.g., disease, their proportion and types determined corn starch) to promote colonic salt and water by the specificity of tissue transglutaminase absorption is an important advance. for deamidating those peptides. This has led to an algorithm for predicting candidate disease- Intestinal barrier function in health activating peptides in the dietary grains known and disease to cause celiac disease. This information can be used to uniquely engineer grains deficient in Research on the function and regulation of potentially disease-activating gluten peptides. tight junctions has led to a better under- standing of their roles in health and disease. Prevalence and phenotype of celiac disease Diseases of junctional proteins can lead to changes in localization or function, which affect For many years, celiac disease was thought to cell polarity, localization of plasma membrane be uncommon in this country. However, several

Diseases of the Stomach and Small Intestine 133 studies have now shown that celiac disease long-term autoimmune and allergic disorders, is very common, estimated to afflict about 3 such as type 1 diabetes, IBD, and asthma. million people in the U.S. or about 1 in 133 Innate immune and genetic mechanisms also people. It is estimated that 1 in 22 individuals contribute to the risk of developing NEC. who have a first degree relative with the TLR4 on intestinal epithelium contributes disease also has celiac disease. Celiac disease to activation of inflammation inNEC. Single can present in different ways, making diagnosis nucleotide polymorphisms have been identified difficult in some individuals. The basis for in key inflammatory mediator genes that different clinical presentations or phenotypes is could contribute to ethnic disparity in various poorly understood. neonatal outcomes, including NEC.

Intestinal immaturity Several clinical studies have shown efficacy of probiotics in treating NEC in the premature Prematurity is the greatest risk factor for infant. Other agents, including platelet- NEC rather than any particular insult, which activating factor acetylhydrolase, epidermal suggests that the fundamental issue may be growth factor, heparin-binding epidermal intestinal immaturity. Studies have focused on growth factor, and , have been identifying aspects of intestinal immaturity tested in animal models of NEC and also show that explain the unique susceptibility of promise as therapeutic candidates for this the premature infant to NEC. The exquisite disease. susceptibility for the initiation of inflammation in the immature intestine compared to the Eosinophils in enteric diseases mature intestine due to inadequate regulation of NF-κB signaling provides an explanation An accumulating body of clinical evidence for the high prevalence of NEC in premature supports a pro-inflammatory role for infants compared to more mature individuals. eosinophils as damaging white blood cells in In addition, immature intestinal vascular intestinal diseases. Eosinophils accumulate regulation contributes to this disease. in the GI tract during allergic inflammation, acid injury, infections, and IBD in response Pathogenesis of necrotizing enterocolitis to chemokines. Involvement of eosinophils in altering intestinal motility and disrupting the The intestinal microflora and its relationship intestinal barrier with subsequent diarrhea to the mucosal immune system are emerging and protein loss is likely related to release of as important components of pathophysiologic specific mediators, including granule proteins processes that cause acute disease, such and other biologically active mediators. as NEC in the premature infant, as well as

134 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases GOALS FOR RESEARCH 15

Research Goal 8.1: Understand mechanisms Research Goal 8.2: Reduce and prevent NSAID and improve treatment of H. pylori diseases. peptic diseases.

H. pylori has been categorized as a Class 1 Peptic diseases caused by NSAID usage could be carcinogen for and is a major risk reduced or prevented entirely by identifying at-risk factor for PUD. Several important issues remain patients, improving patient and physician education unresolved, and there have been reports that H. on the potential complications of NSAIDs, and pylori is inversely related to other diseases, such developing more effective and safe countermea- as esophageal disease and asthma. Research sures. To reach this goal, research is needed to now must be directed toward obtaining a better understand the risks associated with long-term use understanding of the cellular and molecular basis of NSAID and PPIs and to identify the populations of H. pylori-associated diseases, particularly in that are most likely to suffer adverse effects. The defining the role of chronic mucosalinflammation. causes of idiopathic ulcers may be heterogeneous. A Knowledge of the pathogenesis of H. pylori will careful assessment of the proportion of such ulcers enable the rational development and testing of that are due to surreptitious NSAID use would aid in novel therapeutics and optimization of existing the identification of at-risk individuals. Researchers treatments. Importantly, with the falling prevalence have already demonstrated that inhibition of COX-1 of H. pylori, the proportion of idiopathic ulcers is not sufficient for abrogating GI damage induced is likely to increase; the cause of this significant by NSAIDs. Furthermore, 5-lipooxygenase inhibitors minority of ulcers is a new focus of investigation. appear to protect against NSAID-induced injury. By exploiting these and other advances, better drugs Objectives: to treat NSAID-associated acid-peptic diseases or ß Profile the microbial, molecular, cellular, and reduce the risk of complications can be developed. epidemiological features of H. pylori-induced gastric carcinogenesis and PUD to identify Objectives: diagnostic, prognostic, predictive, preventive, ß Define pathogenic mechanisms that regulate and therapeutic targets. NSAID-induced injury. ß Define the relationship betweenH. pylori and ß Develop population-based screening and GERD complications and assess the conse- pharmacogenomic approaches for identification of quences of prolonged PPI use. individuals at risk for NSAID-induced peptic ulcer ß Develop noninvasive technologies to screen for disease as a basis for subsequent intervention. H. pylori-induced pre-malignant lesions. ß Educate patients and physicians regarding risk ß Develop prevention strategies based on mecha- factors and improve adherence to appropriate nisms of H. pylori/host interactions that lead to strategies for decreasing NSAID-associated GI pre-malignant/malignant lesions and evaluate complications. their effectiveness in at-risk populations. ß Determine long-term risks of chronic NSAID usage and PPI therapy, including the risk of neoplasm. ß Design anti-inflammatory agents of comparable or higher efficacy to traditional NSAIDs, but which lack traditional GI side effects and cardiovascular toxicity.

15 Research Goals are numbered for ease of reference only; the numbers do not indicate prioritization of scientific topics.

Diseases of the Stomach and Small Intestine 135 Goaloalss for for Rese Rarcesearchh

Research Goal 8.3: Define the genetic, Objectives: bacterial, and host factors that regulate epithelial ß Develop more sensitive methods for detecting and inflammatory cell responses to injury in gastric gastrinomas and metastases. mucosa. ß Develop a reliable mouse model of gastrinoma that mimics features of ZES, specifically The mechanisms that underlie gastric mucosal duodenal tumors. responses to pathogens and injurious agents are incompletely understood. By defining the genetic, molecular, and cellular bases for gastric mucosal Research Goal 8.5: Determine the genetic, injury and repair, novel therapies can be developed molecular, and integrated physiologic bases of to prevent or more rapidly recover from acid-peptic intestinal water, nutrient, and electrolyte transport. diseases. Despite the prevalence and other impacts of Objectives: diarrheal diseases, their disease mechanisms are ß Elucidate genetic, bacterial, and host factors not well understood. Experimental models to probe that regulate or affect gastric mucosa response the genetic, molecular, and integrated physiologic to pathogens and stress. bases of intestinal water, nutrient, and electrolyte ß Understand mechanisms of mucosal cytopro- transport are inadequate. Most knowledge has tection and wound healing. been gained at the cellular and membrane level, ß Develop novel therapies that promote mucosal where key transporter molecular and their associated cytoprotection and wound healing. regulatory signaling pathways have been partially elucidated. Currently available molecular and genetic approaches make it possible to unravel the Research Goal 8.4: Understand the basis of complexities of protein and molecular interactions rare gastric cancers, develop effective measures for involved in enterocyte transport, although the cost earlier and more accurate diagnosis, and develop of using these technologies may be prohibitive. effective treatment strategies. (See also Goal 4.12.) Noninvasive methods are needed to study in vivo the function and regulation of intestinal absorptive and More information regarding the carcinogenic digestive processes, including visualizing the signal process of less common gastric cancers, such as transduction pathways and genes involved in normal gastrinomas, would accelerate the development of absorption/digestion and their integration (in humans strategies for early diagnosis and for more effective and animals). This line of research will lead to better treatment. For example, improved understanding understanding and treatment of diarrheal diseases, of the correlation between mutations in the menin particularly chronic diarrhea, for which treatment is gene and patient phenotypes would help in the often purely symptomatic and limited. development of effective treatment strategies that are tailored to subgroups of patients. Identifying Objectives: other genetic loci that regulate the development of ß Identify and characterize proteins involved in gastrinomas would also improve the classification intestinal transport function, such as of patient and disease sub-types. transport proteins and transport proteins in the basolateral membrane of sodium absorptive cells involved in moving amino acids, sodium, chloride, or heavy metals into blood, as well as

136 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Goals for Research

signaling molecules and accessory proteins that ascertained. Improvements are needed in treatment, regulate the activity, expression, trafficking, prevention, and diagnosis of malabsorptive and membrane abundance, and degradation of diarrheal diseases. Developing noninvasive methods these transport proteins. to study normal digestive and transport processes, ß Understand the processes that allow coordi- as well as their regulatory systems and integration, nation of motility, absorption, and secretion is crucial for research in this area. Likewise, new in the intact intestine of animal models and approaches to studying patients with these humans. Determine how changes in sodium conditions would enhance our understanding of absorptive and chloride secretory processes are small bowel bacterial overgrowth and diarrheal, integrated with changes in tight junctions. maldigestive, and malabsorptive disorders. Finally, ß Determine the proteome of the intestinal research is needed to understand the causes, sodium absorptive cell and chloride secretory pathophysiology, and treatment of chronic diarrheal cell, including the subcellular proteome of brush diseases and to develop clinically useful imaging and border and basolateral membrane under normal diagnostic technologies. conditions and in diarrhea and malabsorption. ß Characterize the effects of knocking out Objectives: enteroendocrine cells on the development ß Determine the causes of chronic diarrheal of the gut and on integrative aspects of diseases in the 40 percent of patients in whom absorptive, secretory, and digestive functions no specific cause is identified; it is expected of the intestine. Determine how maldigestive that some will be due to polymorphisms and/or states affect normal gut development and mutations in intestinal transporters. Determine differentiation of the genes involved in nutrient the epidemiology of acute diarrhea in the elderly, digestion and transport. including mortality. ß Identify bacteria that are present in the normal ß Develop preventive measures to limit the human small intestine and colon and the incidence of acute diarrheal diseases. Evaluate changes that occur in bacterial overgrowth, the role of non-hydrolyzable starch-based ORS in Crohn’s disease, microscopic colitis, eosinophilic treatment of acute diarrhea in adults and children enteritis, celiac disease, other malabsorptive in developing countries and the U.S. diseases, lactase deficiency, andobesity. ß Develop clinically useful imaging and diagnostic ß Determine the contribution of paracellular techniques to examine digestive processes and transport of luminal materials to intestinal abnormalities in diarrheal and malabsorptive disease, characterize how tight junctions limit diseases. specific molecule movement, and understand ß Test new anti-chloride-secretory and pro- the integration of cellular and paracellular sodium-absorptive drugs in animal models of movement and regulation of movement. acute diarrheal diseases. Conduct clinical trials to test these agents in patients with acute diarrhea. ß Develop gene therapy targeting intestinal Research Goal 8.6: Improve treatment, epithelial cells and pharmacologic agents capable prevention, and diagnosis of malabsorptive and of blocking or augmenting pathways that control diarrheal diseases. intestinal gene expression as part of future treatment strategies for chronic diarrheal and Clinically, the prevalence and impact of acute malabsorptive/maldigestive diseases. diarrheal diseases on the elderly must be

Diseases of the Stomach and Small Intestine 137 Goaloalss for for Rese Rarcesearchh

Research Goal 8.7: Understand pathogenic ß Definethe role of antibodies and immune mechanisms of celiac disease, autoimmune diseases, complexes in celiac disease. and allergic diseases of the digestive system. ß Define the potential role of intestinalmicroflora in the pathogenesis of celiac disease and Identification of molecular pathways supporting autoimmune and allergic disorders of the bowel. the critical role of innate immunity has transformed ß Define signaling pathways (e.g., , our understanding of the pathogenesis of celiac MLCK, enteric toxins, cytokines) that are disease. It is now evident that the interplay involved in the regulation of intestinal perme- between adaptive and innate immunity is critical ability under physiologic and pathophysiologic at all steps of the disease. Furthermore, several conditions. observations suggest that transglutaminase is ß Distinguish between the effects of the IL-23 and in an inactive state in the intestinal mucosa of IL-12 pathways in the pathogenesis of chronic patients with the disease. The events leading to GI inflammation. transglutaminase activation remain poorly under- ß Determine the basis of refractory celiac disease. stood. Finally, the role of antibodies and immune complexes in initiation and development of celiac disease have not been sufficiently investigated. Research Goal 8.8: Improve screening, Our understanding of genetics, host responses, and diagnosis, prevention, and treatment of celiac tissue injury in response to gluten has increased disease and of autoimmune and allergic disorders substantially, but is far from complete. A major of the bowel. Characterize and define the mecha- limitation in studying celiac disease is the lack of nisms underlying the association of celiac disease suitable animal models. with autoimmune and neurological diseases. (See also Goal 2.11.) A good understanding of disease pathogenesis in autoimmune and allergic disorders of the bowel Celiac disease is common, but often unrecognized is lacking. Potential contributors to these diseases until severe enteric and systemic complications that warrant further exploration include risk occur. Furthermore, the clinical presentations factors, gut development, innate and adaptive of celiac disease are diverse and may be linked immunity, the enteric microflora, and intestinal to different effector mechanisms. For instance, barrier function. immune complexes may underlie the pathogenesis of and gluten-associated Objectives: neurological diseases, whereas pathologic T cells ß Define theearly innate events and the interplay mediate epithelial cell destruction and enteropathy. between innate and adaptive immunity in celiac In addition, subclinical presentations of celiac disease disease pathogenesis. remain poorly characterized. In particular, several lines ß Elucidate the events leading to transglutaminase of evidence suggest that the presence of anti-trans- activation and define its role inceliac disease glutaminase antibodies does not imply the presence pathophysiology, both as an autoantigen and as of intestinal lesions and enteropathy. Conversely, a modifier of toxicgluten peptides. gluten-induced innate events may lead to epithelial ß Define mechanisms and events that link the cell alterations associated with clinical symptoms in generation of large gluten peptides and the the absence of anti-transglutaminase antibodies. ultimate development of pathogenic T cell Finally, celiac disease is strongly associated with other populations. organ-specificautoimmune diseases, particularly type 1 diabetes. The molecular mechanisms underlying

138 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Goals for Research

this association remain poorly understood. Many Research Goal 8.9: Understand the pathogenesis physicians and medical staff members are unaware of necrotizing enterocolitis and the unique susceptibility of the prevalence and clinical manifestations of of the premature infant, including genetic susceptibility, celiac disease. A better understanding of the microflora, and immune/inflammatory processes. seemingly protean nature of clinical, histological, and immunological presentations of celiac disease will The exquisite susceptibility for inflammation of help improve the diagnosis and treatment. Novel and the immature intestine compared to the mature effective therapeutic and preventive strategies are intestine provides an explanation for the high now possible through the insights gained over the prevalence of NEC in premature infants compared past few years of research on disease pathogenesis. to more mature individuals. The intestinal microflora and its relationship to the immature Allergies and hypersensitivity to food are common, mucosal immune system are emerging as important yet poorly understood. In some cases, allergies to components of pathophysiologic processes that foods, such as nuts or shellfish, can be life-threatening cause acute disease, such as NEC, in the premature and require immediate medical attention. Molecular infant, but may also play a role in intestinal and immune mechanisms that underlie food allergies maturation. Several studies suggest that manipu- are not well understood and are inadequately studied. lation of the intestinal microflora with probiotics is beneficial. Despite a paucity of information Objectives: on deleterious side effects, there is concern that ß Develop a more complete understanding of the introducing live microbes might result in long-term pathogenesis of celiac disease, including the role of complications. Studies have suggested that Toll-like immune, epithelial, microbiological, environmental, receptor (TLR) ligands or other non-live microbial and host factors, as well as its relationship to other components provide benefits similar to those of live autoimmune diseases. bacteria without deleterious effects, but additional ß Identify novel biomarkers, including additional investigation is needed. genetic risk factors, to predict the development of in high-risk patients and Objectives: to determine severity of illness and response to ß Develop models of immature gut relevant to the treatment. development of NEC. ß Identify environmental triggers of celiac disease. ß Investigate the development of intestinal host ß Identify new, noninvasive methods to diagnose defense mechanisms and the intestinal immune celiac disease. system relevant to NEC. ß Develop non-dietary methods to treat celiac ß Define normal patterns of bacterial colonization disease. in the healthy premature infant relevant to NEC. ß Establish the safety/efficacy and benefits of thera- ß Understand the role that appropriate microbial peutic interventions that improve intestinal barrier balance plays in intestinal development. function in patients with autoimmune diseases ß Identify mechanisms responsible for probiotic and identify the autoimmune pathologies (GI and effects on acute gut injury in premature infants. non-GI) that may benefit from such interventions. ß Identify the mechanisms underlying food allergies and develop simple and accurate tests to identify food allergy or hypersensitivity.

Diseases of the Stomach and Small Intestine 139 GOALS FOR RESEARCH

Research Goal 8.10: Develop novel predictive, Research Goal 8.11: Determine the genetic therapeutic, and preventive approaches for bases, mechanisms, natural history, and clinical necrotizing enterocolitis. phenotypes of eosinophilic gastrointestinal disorders and identify/develop novel therapeutic compounds. Although several compounds have recently shown promise in the prevention of NEC in rat and mouse It is now recognized that eosinophils play an models of the disease, many hurdles remain to important role in inflammatory diseases of the testing these agents in human infants. Nonetheless, upper GI tract. However, the mechanisms by which several agents warrant further investigation eosinophils disrupt normal GI physiology and cause in clinical settings. Development of predictive disease are incompletely understood. Defining biomarkers, including polymorphisms or other genetic profiles, understanding the natural history of parameters, for at-risk infants is a priority. Improved disease, and developing more specific and effective understanding of predisposing genetic or other treatments for EGIDs are critical research goals. biomarker traits will enhance identification of at-risk infants and could lead to improved approaches for Objectives: preventing and treating this disease. ß Define the genetic bases,epidemiology, and natural history of EGIDs. Objectives: ß Define clinical phenotypes of EGIDs (e.g.,allergic, ß Complete phase I and phase II trials in the U.S. non-allergic, or autoimmune) and develop novel of promising therapeutic interventions to assess animal models and reagents to study eosinophilic and dosing strategy in premature GI inflammation. infants, including platelet-activating factor ß Define cellular and molecular pathways that acetylhydrolase, probiotics, and factors found in regulate -dependent tissue remodeling. human milk. ß Identify and develop novel agents for treatment ß Develop other novel therapies or preventive of EGIDs, such as anti-IL-5 antibody, anti-CCR3 measures based on discoveries made in under- receptor antibody, and imatinib. standing NEC pathophysiology and causes. ß Investigate the mechanisms behind and possible interventions to prevent the poor neurodevel- opmental outcomes of infants with NEC. ß Investigate the role in NEC development of clinical practices, such as the use of H2 blockers, opioids, indomethacin, umbilical , treatment of patent ductus arteriosus, and feeding patterns. ß Develop programs to encourage breast milk feeding of premature infants.

140 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases MAJOR CHALLENGES AND STEPS history of pre-malignant lesions. Mechanisms TO ACHIEVE the RESEARCH GOALS to coordinate research and management of a range of diseases (e.g., rare gastric tumors, ZES, Animal models: Development of robust dyspepsia, chronic diarrheal and malabsorptive animal and cell models would accelerate diseases, NEC, celiac disease, and eosinophilic scientific progress on both normal gastric and gastroenteritis) would secure the critical mass small intestinal physiology, as well as the of cases needed for scientific advancement. Such pathophysiology underlying a wide spectrum multicenter networks could pool biosamples of diseases that affect these organs. Research and patient data and implement guidelines areas that would benefit from experimental for clinical practice. Small conferences would models that faithfully replicate human disease support clinical and scientific interactions that include H. pylori-induced gastric cancer and could spark innovative approaches to research ZES, intestinal transport, malabsorption, on these diseases. maldigestion, celiac disease, autoimmune and allergic diseases of the bowel, and NEC. Central research resources: The estab- In addition, development and optimization of lishment of centralized resources, including animal models to study infection, morphologic databases, patient registries, and biosample interpretation of lesions, imaging technology, repositories, would support and facilitate basic cellular processes such as , multicenter collaborations. The creation of migration, and ion transport in intestine, databases, with an emphasis on enrollment of and drug testing will foster innovative minority gastric cancer patients, and specimen research approaches to understand and and tissue banks would fill an important treat GI diseases. Related resources, such as gap. Large-scale biology approaches could be improved organ cultures, organotypic culture developed to identify protein-protein interac- technologies, and H. pylori strain repositories, tions as well as pH and calcium homeostasis would also strengthen the field. within sodium-absorptive, chloride-secretory, and enteric endocrine cells during digestion Clinical research collaboration: For less and in diarrheal diseases. Similarly, devel- common diseases (e.g., gastrinomas, genetic opment of centralized repositories of clinical diarrheal disorders) or complex disorders (e.g., data and samples (e.g., serum, intestinal tissue, dyspepsia, celiac disease, IBD, NEC), single cDNA) from celiac disease or eosinophilic institutions lack sufficient numbers of cases, gastroenteritis patients could be used by inves- biospecimens, research resources, or therapeutic tigators across the country to gain insights capabilities. The establishment of multicenter, on the pathogenesis of these diseases and systems biology-based consortia or networks to explore alternative treatments. A similar of healthcare professionals to share materials repository for autoimmune patient samples and information and increase statistical power or databases on families with high incidence would accelerate research in these diseases. For of autoimmune diseases would serve as example, the lack of information on cost-effective valuable resources for clinical and basic science prevention of H. pylori or NSAID-induced injury investigators in the field. Indeed, research could be addressed through interdisciplinary, on many diseases of the stomach and small population-based, endoscopic, multi-institu- intestine would benefit from the availability tional studies to identify H. pylori-infected of centralized, accessible resources for patient populations at greatest risk for gastric cancer samples and data. and to determine the prevalence and natural

Diseases of the Stomach and Small Intestine 141 Physician communication and education: expression vectors, or integrative models Inadequate interaction and communication of gut absorptive and digestion function occurs between adult and pediatric clinicians in humans would open up new avenues of who treat diseases of the stomach and small research. Technology and scientific methods intestine. Small conferences could promote for evaluation of microbial ecology are rapidly interactions between adult and pediatric emerging, but communication between basic clinicians to define thenatural history of these scientists developing the technology and diseases. In addition, there is poor adherence clinical scientists who are able to bring these to guidelines or “best practices” (e.g., protective technologies to the patient could be enhanced. strategies in high-risk NSAID users) in Finally, refinement ofgenomic and proteomic treatment of acid-peptic diseases. Programs techniques to identify biomarkers using human could be developed that determine causes, intestinal samples would be useful in many make appropriate recommendations, develop intestinal diseases, including NEC. mechanisms to disseminate recommendations, assess whether recommendations are being Drug development: Many intestinal followed, and assess alterations in outcomes diseases lack effective therapies. Therefore, (quality-of-care). Because celiac disease is so new drug development, which is an expensive prevalent but under-recognized, educational and time-consuming endeavor, could benefit campaigns, such as the NIH Celiac Disease from collaboration between academia and the Awareness Campaign, have the potential to pharmaceutical and biotechnology industries. increase awareness of this disease among For example, the dearth of anti-diarrheal drugs healthcare professionals. could be addressed by developing programs, possibly through partnership with industry, to Innovative technologies: Experimental better understand diarrheal pathogenesis and tools and models to study gastric and intestinal to develop novel therapeutic compounds. High- epithelial physiology and diseases, including throughput screening of anti-diarrheal drugs peptic diseases, H. pylori pathogenesis, that inhibit chloride secretion and/or stimulate diarrhea, malabsorption, development, sodium absorption could result in the identi- inflammation, and pediatric disorders are fication of promising compounds. Similarly, lacking. Investment in infrastructure to collaboration with industry to develop specific develop proteomic approaches to study GI microbes (probiotics) or microbial products that disease would promote progress across the stabilize the intestinal mucosal immune system field. The development of new methods to and mutual funding of multicenter trials could target epithelial cells or GI tissues with siRNA, accelerate the search for therapies for NEC.

142 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Diseases of the Stomach and Small Intestine 14 Digitally enhanced x-ray of a human colon outlined using barium contrast material. Several diverticula, or bulges protruding from the colon wall, are visible in the distal colon.

Image Courtesy of Scott Camazine/ Photo Researchers, Inc.

 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Diseases of the Colon and Rectum

SUMMARY OF RESEARCH GOALS

The colon and rectum are susceptible to a variety of diseases and conditions that can impair their primary functions of maintaining water balance and eliminating wastes. The Commission’s proposed research goals are aimed at understanding mechanisms of colonic injury, repair, and function so that prevention and treatment strategies for these disorders can be optimized. Key topics for research on colonic diseases are elucidating the role and composition of the gut microflora and manipulating this microbial community to restore health. Studies are also needed to establish the basis for structural defects like diverticular disease and vascular disorders, such as colonic ischemia (CI) and angioectasias. Better means of detection and treatment would improve the health and quality of life of elderly individuals, who are most affected by these conditions. Research is urgently needed on anorectal disorders, including anal fistulas, hemorrhoids, andfecal incontinence, which lack a firm evidence base concerning the causes and effective management strategies for these common, but poorly studied, conditions. Research on ways to prevent and treat radiation injury of the colon would alleviate this treatment-induced complication of pelvic cancer therapy. Finally, appendicitis can be fatal if undiagnosed and untreated. Research on the risk factors for onset and progression of appendicitis would further reduce the burden of this condition, especially in children.

Diseases of the Colon and Rectum 145 INTRODUCTION AND BACKGROUND absorption as a result of colonic injury or disease can result in constipation or diarrhea The human colon—or large intestine—is if too much or too little water is absorbed. primarily responsible for absorbing remaining Chronic diarrhea can result in dehydration water from indigestible food matter that and malnutrition; constipation (see also has passed through the small intestine, the chapter on Functional Gastrointestinal maintaining the water balance in the body, Disorders and Motility Disorders) may lead to and absorbing some vitamins. The final the development of hemorrhoids, , section of the luminal digestive tract—the or . rectum and anus—eliminates wastes from the body. Diseases involving the colon and Gut microflora: The human intestinal rectum are diverse and include anatomic tract is colonized by a complex and diverse conditions (e.g., diverticular disease, fistulas, community of microbes that are essential to fecal incontinence), blood flow or vascular the normal digestive functions of these organs. disorders (e.g., CI, angioectasias, hemorrhoids), Little is known about the interaction of the conditions related to the gut microflora or majority of these microbes and their role— immune dysfunction (e.g., inflammatory bowel individually and collectively—in health and disease [IBD], appendicitis), treatment-related disease due to technical limitations in isolating disorders (e.g., radiation colitis), and colorectal and culturing individual species in the cancer, gastrointestinal stromal tumors laboratory. Advances in genomic and proteomic (GIST), carcinoids, and other cancers affecting technologies coupled with the prior knowledge the colon and rectum (see also the chapter on of these organisms are set to revolutionize Cancers of the Digestive System). the characterization of the gut microflora. Bacteria in the colon produce small amounts Colonic mucosal injury and repair: The of some vitamins, including vitamins K and B, colon and rectum are lined with epithelial which are absorbed through the walls of the cells that absorb water and nutrients from colon. Alterations in the balance of species in undigested material and secrete a thick mucus the gut are linked to such diverse conditions layer that protects the lining from invasion by as obesity, IBD, colitis (inflammation of the the gut microflora. Colonic epithelial cellinjury colon), and sepsis. Approximately 20 percent of requires both restitution and regeneration hospitalized patients who receive an antibiotic (proliferation). Rapid restitution of the mucosal will become colonized by the pathogenic epithelium is crucial to quickly restore the bacterial species, Clostridium difficile, and epithelial barrier, thereby limiting fluid and many will develop severe colitis. C. difficile is electrolyte losses, as well as preventing the kept from colonizing the colon by the normal introduction of harmful bacteria and foreign microflora, and restoration of the microflora antigens. In response to colonic injury, goblet following infection is thought to result in cells of the mucosa secrete a small protease- eradication of the pathogen, which, if proven, resistant peptide, termed trefoil factor 3 would indicate a vital role of the microflora in (TFF3) peptide. maintaining the health of the colon.

Colonic mucosal absorption and colon Diverticular disease: In Western society, vasculature: A primary function of the many older people develop pockets, or colonic mucosa is to absorb water and “diverticula,” that bulge outward from the electrolytes from undigested materials colon wall, a condition known as . before elimination. An imbalance in mucosal While some people have no symptoms of

146 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases diverticulosis, others may experience mild abscess and the surface of the skin. A surgical discomfort, bloating, or constipation. Infection procedure known as a fistulotomy can remove or inflammation of the diverticula results both the fistula and the original abscess. in , a more serious condition Hemorrhoids are inflamed in the lower associated with abdominal pain, bleeding, rectum that may cause pain or rectal bleeding. infections, perforations, or blockages. In Treatments options include over-the-counter extreme cases, abscesses may form in the creams, oral pain medications, or surgery colon wall, leading to or fistulas. to remove the tissue or cut off blood flow to Diverticular disease is thought to develop as the . Fecal incontinence, or the a result of a low-fiber diet and is treated by inability to control the bowels, affects up to 5.5 a high-fiber diet, mild pain medications, or million people of all ages in the U.S. and can be surgery. treated by dietary changes, medications, bowel training, or surgery. and angioectasias: Inadequate blood supply to the colon can Radiation colitis: Radiation therapy for lead to inflammation andinjury, a condition cancers of the can damage the known as ischemic colitis. The majority of epithelial lining and blood vessels of the cases occur in elderly patients over 60 years of colon, resulting in radiation colitis. This age. Blood clots or low blood pressure account inflammatory condition, which can develop for some cases of ischemic colitis, although within weeks or years after exposure to x-rays in many patients the cause is unknown. Mild or ionizing radiation, causes symptoms that cases of ischemic colitis may resolve without may include abdominal cramping, diarrhea, medical intervention. More severe cases can nausea, vomiting, rectal bleeding, and others. lead to sepsis, intestinal gangrene, or bowel In severe cases, patients may experience perforation and require surgical care. CI is complications, such as intestinal blockage, the most frequent ischemic disorder of the infection or abscess, nutritional deficiencies, or GI tract. Epidemiologic studies have been bowel rupture. Treatment for radiation colitis designed to answer the question of whether may involve changes to the diet or medications CI has a positive association with irritable or, in very rare cases, surgery to bypass or bowel syndrome (IBS) or whether such an remove the colon. association results from medications used to treat IBS. These studies have shown that CI Appendicitis: Appendicitis is an inflam- has an estimated crude incidence rate of 7.2 mation of the appendix, a small, closed-end per 100,000 in the general population. Part of tube attached to the first segment of the the difficulty in determining the incidence of colon on the lower right side of the abdomen. CI, however, is the difficulty in diagnosing it. When the opening of the appendix is blocked, bacteria normally found in the appendix may Anorectal disorders: Disorders of the anus begin to infect the walls of the organ and and rectum are usually not life-threatening, trigger an immune response. This blockage can but can have significant impact on a person’s occur with fecal matter, lymphoid aggregates, quality of life. Anal fissures—cracks or tears in torsion, or a tumor with subsequent bacterial the skin of the anus—are usually superficial overgrowth. This leads to bacterial invasion of and easily treated. However, chronic fissures the appendiceal wall, inflammation, ischemia, that expose the underlying muscle may gangrene, and perforation. Organisms typically require surgical intervention. An identified include E. coli, Peptostreptococcus is a pathway that develops between an anal species, B. fragilis, and Pseudomonas species.

Diseases of the Colon and Rectum 147 If left untreated, the appendix can rupture, development of new, non-immunomodulatory allowing the infection to spread throughout approaches to symptom relief and mucosal the abdominal cavity. Appendicitis can be healing. treated with surgical removal of the appendix and antibiotic therapy to control the infection. Diversity of sodium absorptive pathways Approximately 325,000 cases of appendicitis and complexity of their molecular occur each year in the U.S., primarily in the regulation second decade of life. Research advances include the development of transgenic mice lacking expression of selected RECENT RESEARCH ADVANCES sodium-hydrogen exchange isoforms, coupled with new data regarding their molecular Effect of intestinal microflora on repair assembly as multi-protein complexes that of the colonic epithelium regulate via rapid alterations in surface expression. These advances have highlighted the A greater understanding of the basic biology of need for more comprehensive understanding of TFF3 and other intestinal growth factors will the factors responsible for the coordinated fine- advance our knowledge of how the gut responds tuning of polarized ion transporters to affect the to injury to begin the rapid repair process. In balance of secretion and absorption in the colon addition to restitution, the gut epithelium must during health and disease. also begin the process of regeneration, which involves repopulation (via proliferation) of the The influence of luminal factors on colonic mucosal absorption mucosa with new epithelial cells. The discovery that enteric bacteria promote proliferation of Major luminal anions (e.g., short chain fatty epithelial cell progenitors at sites of colonic acids [SCFAs]) and cations (e.g., ammonia) are mucosal injury, via their Toll-like receptor bacterial fermentation products of (TLR)-specific interactions with newly recruited and protein that have been shown to affect not macrophages, has proven to be a major advance only colonic absorptive transporter expression in understanding the relationship among and function, but also mucosal growth and enteric microflora, the innate immune system, differentiation through genetic and epigenetic and epithelial repair. mechanisms. The recent identification of novel Alterations in colonic sodium absorption transporters, including MCT transporters underlie diarrheal responses in colitis and Rh transporters, illustrates the complexity of colonic handling of these It has become clear that diarrheal substances. The presence of multiple manifestations of colitis are due to selective transporters for SCFAs and ammonia suggests inhibition of sodium-absorptive ion transport an important interrelationship among pathways rather than activation of chloride- diet, luminal microflora, and mucosal fluid secretory pathways, as had been assumed in homeostasis. the past. Moreover, manipulation of sodium and chloride transport pathways appears to Extreme diversity of the human gut microflora impact restoration of mucosal barrier function following injury. These findings suggest that Most textbooks suggest that the human colon understanding the segmental heterogeneity of harbors approximately 20-30 genera and ion transport pathways and their alterations 400-500 species, with a total population at least during inflammation may lead to the

148 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases 10-fold that of somatic cells. These numbers concept could be exploited to manipulate the were generated by traditional bacteriologic microflora to influence bodyweight. techniques that relied on specialized culture media to isolate, characterize, and identify Extracellular matrix remodeling in individual species. Recent studies using modern patients with diverticulosis genetic techniques provide a much more complex picture of the intestinal microflora. The feces of Factors involved in the pathogenesis of healthy subjects contain thousands of bacterial diverticulosis include relatively low dietary species, mostly novel, uncultivated organisms. fiber intake and decreased tensile strength Considerable diversity in the gut microflora of collagen and muscle fibers in the colonic exists between individual humans, suggesting wall as a result of aging. Research suggests the possibility that each person may harbor that decreased tissue levels of matrix a distinctive repertoire of bacterial species in metalloproteinases, which are involved addition to common shared species. Adherent in extracellular matrix degradation bacteria form a thin biofilm attached to the and remodeling, and tissue inhibitors of epithelial surface. This mucosal population metalloproteinases may contribute to the differs greatly from the fecal population structural changes in the colonic wall seen in inhabiting the lumen and is quite diverse patients with diverticular disease. in different parts of the colon, suggesting considerable “patchiness” in composition. Alteration of nervous system and smooth muscle activity in diverticulosis Human and murine microbes associated with obesity Patients with diverticulosis have reduced numbers of colonic interstitial cells of Cajal The human and mouse microflora consist of and enteric glial cells, but normal numbers two main phyla: Bacteroidetes and Firmicutes. of enteric neurons, compared with healthy The former phylum includes 20 distinct controls. These changes may decrease colonic genera, of which Bacteroides species are the electrical slow-wave activity, thereby resulting most abundant. Firmicutes include such well- in delayed transit and possibly contributing to known genera as , Bacillus, increased intraluminal pressure. In addition, and Clostridium species. Recently, important these patients exhibit loss of colonic smooth differences were shown between the relative muscle choline acetyltransferase activity, up- abundance of these two phyla in lean compared regulation of muscarinic M3 receptors, and to obese humans. Obese humans had more increased in vitro sensitivity of the smooth Firmicutes and fewer Bacteroidetes than muscle to exogenous acetylcholine (cholinergic lean people. During weight loss on either a denervation hypersensitivity). This finding low- or low-fat diet, the relative may explain increased colonic contractility in composition of these two components shifted patients with diverticulosis. to fewer Firmicutes and more Bacteroidetes. Similar studies in obese mice showed that the Visceral hypersensitivity in microflora ofobese mice were more effective at diverticular disease extracting calories from food, allowing increased energy recovery for the host. These important Heightened visceral perception to rectosigmoid studies suggest that differences in the intestinal distention has been found in patients with microflora can potentially regulate energy symptomatic diverticular disease, but not availability and recovery from non-digestible in those with asymptomatic diverticulosis. nutrients in the gut lumen. This revolutionary Evidence suggests that the visceral

Diseases of the Colon and Rectum 149 hypersensitivity may relate to release of seen in elderly patients with major episodes proinflammatory mediators that sensitize of lower intestinal bleeding. Angioectasias are enteric afferent nerve terminals and, thereby, seen in up to 32 percent of patients with aortic heighten the response to noxious stimuli. stenosis, suggesting a relationship with cardiac valvular disease, perhaps via abnormal von Treatment for inflammation in Willebrand factor multimers, resulting in a diverticular disease predisposition to bleed.

Based on the possible role of low-grade colonic Etiology and treatment of fecal incontinence inflammation in symptomatic uncomplicated diverticular disease, trials have been undertaken Incontinence of stool is more common than of the non-absorbable antibiotic rifaximin, the previously thought, with a prevalence of anti-inflammatory agent mesalamine, and 2-15 percent, depending upon the population probiotic and prebiotic agents. Preliminary studied. Continence for stool is a complicated results suggest that these agents, particularly process; recent work focuses on the contribution rifaximin and mesalamine, may reduce of obstetrical injury and aging to fecal symptoms and prevent relapses, especially in incontinence, but our understanding is still patients with recurrent diverticulitis, although limited. New treatment modalities, including the benefit may be marginal. the artificial bowelsphincter and sacral nerve stimulation, show promise for patients with Colonic vasculature injury in fecal incontinence. Crohn’s disease

Treatment of perianal fistulas The cause of CI is rarely apparent, and most cases are believed to result from The prevalence of perianal fistulas in patients localized episodes of non-occlusive ischemia. without IBD is not well described. Depending A hyper-reactivity of the colonic arterial upon the location of intestinal disease, microvasculature is suggested by the 25-50 percent of patients with Crohn’s disease approximately six-fold increased incidence in have perianal fistulas. The mechanism of patients with IBS. A venous abnormality is development of perianal abscess and fistula is suggested by the finding of increased incidence poorly understood. Anal fistulas may be cured of various forms of in patients with fistulotomy (unroofing the fistula tract), but with CI. Segments of bowel removed for the procedure carries a significantrisk of fecal Crohn’s disease show a spectrum of vascular incontinence. For patients with Crohn’s disease, injuries, suggesting that the pathogenesis of the use of immunomodulators has significantly Crohn’s disease includes multifocal . changed the treatment of perianal fistulas. For Additional evidence for this hypothesis is patients with cryptoglandular fistulas, new found in the observation that the majority of treatment modalities, including the use of fibrin granulomas in Crohn’s disease form within the glue and plugs, have been developed to cure the walls of blood vessels. fistulas without therisk of fecal incontinence. Relation of angioectasias and cardiac disease Advances in treatment of hemorrhoids

Vascular lesions of the colon, especially In phone surveys, 20 percent of respondents angioectasias, are not an uncommon finding in noted bothersome anal symptoms. Poor the healthy elderly colon and are more commonly patient and provider understanding of

150 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases anorectal anatomy and pathology lead to Treatment for chronic radiation proctitis frequent misdiagnosis and treatment of anal symptoms. Because of the pain associated with Chronic radiation colitis/proctitis is most recovery from conventional hemorrhoidectomy, commonly characterized by rectal bleeding with innovations in this treatment area have mucosal pallor, multiple large telangiectasias, been sought. Stapled hemorrhoidectomy is and strictures. Chronic injury is secondary to a new technique for treatment of prolapsing epithelial atrophy and fibrosis associated with internal hemorrhoids. Division of the internal endarteritis and resultant ischemia. Argon sphincter (i.e., lateral internal sphincterotomy) plasma coagulation has been demonstrated is the standard surgical treatment for anal to decrease rectal bleeding and improve fissures. Because of the risk of post-operative within a few sessions with minimal fecal incontinence, new treatments have been complications. Formaldehyde has been used for developed, including calcium channel blockers several years for treatment, with recent studies and Botox injections. demonstrating efficacy and ease of application with flexible . Good response to Innovations in radiation therapy to single applications has been noted. reduce radiation proctitis Pathophysiology of appendicitis Newer techniques of radiation therapy using computer-based treatment optimization, Fiber intake and resultant constipation intensity-modulated radiation therapy allow have been evaluated in the pathophysiology for variation in the dose in a specific field, of appendicitis. Studies of children with facilitating the sparing of normal tissue appendicitis showed that they have less fiber (i.e., rectum) with a resultant decrease in in the diet. Other studies have revealed that acute radiation proctitis. Higher doses with children in Western countries have low fiber increased efficacy have been associated content in their diets, which is associated with a decrease in complications. Moreover, with constipation. Dietary fiber intake in cytoprotective agents have been found the young is associated with increase and to reduce toxicity without compromising maturation of microbial mass, volatile fatty radiation efficacy. Amifostine, an agent acids, and lower pH. These changes in animal that protects tissues from the cytotoxic models correlate with fewer GI disorders. actions of radiation and chemotherapy that Prebiotics—non-digestible food ingredients was developed by the military for use as that benefit the host by affecting the activity a radioprotectant in the event of nuclear or growth of gut bacteria—may have a similar warfare, has selective cytoprotective effects effect on gut microflora. Agents like for normal tissues. Parenteral and intrarectal and fructooligosaccharides are fermentable amifostine is effective in preventing radiation and selectively increase the growth of proctitis without reducing efficacy. Local bifidobacteria. These agents are fermented agents include balsalazide, a non-absorbable primarily in the proximal colon near the salicylate that has demonstrated clinical appendix. efficacy in management of radiation injury. Sulfasalazine has not been consistently A small study of patients with gangrenous and effective in clinical trials, though it is phlegmonous appendicitis showed a different recommended by some clinicians. cytokine profile. Researchers observed a

Diseases of the Colon and Rectum 151 positive correlation of gangrenous appendicitis appendectomy. Thus, individual differences in with Th1-mediated immunity with higher tendency toward Th1-mediated immunity with levels of interferon-γ and IL-10 when the cytotoxic consequences may determine the patients were studied at least 6 months after outcome of appendicitis.

GOALS FOR RESEARCH 16

Research Goal 9.1: Establish mechanisms ß Identify other gut-specific growth factors capable of of colonic injury and repair to use as a basis for promoting colonocyte restitution and repair. development of therapeutic interventions. (See also ß Develop TLR agonists that mimic the protective Goal 1.6.) effect of enteric bacteria.

The interior lining of a healthy colon regenerates continuously to replace old or damaged cells. Research Goal 9.2: Understand colonic mucosal Understanding the mechanisms that regulate this absorption in health and disease. (See also Goals 1.11 normal cellular turnover will allow researchers to and 1.12.) develop therapies that stimulate the regenerative process to repair colonic tissues damaged by infection, Absorption of water and electrolytes in the colon is inflammation, radiation, or other adverse events. necessary for maintaining proper hydration of the body Molecules such as TLRs, TFFs, and other growth and recovering vital micronutrients from ingested food. factors appear to play a role in proliferation of the Nearly all individuals throughout the lifespan experience mucosal epithelium and represent prime candidates for occasional acute bouts of diarrhea or constipation. drug discovery and development. These conditions are often easily treated with lifestyle or dietary modifications or by the use of readily available Objectives: over-the-counter medications. However, some people ß Identify the specific interactions (e.g., via receptors/ develop chronic disease that can severely affect their ligands) between enteric microflora and TLRs that nutritional status and quality of life. By investigating promote -dependent proliferation of the molecular mechanisms that govern mucosal progenitor cells and determine which mediators absorption, researchers can better understand how released by macrophages are required for epithelial these mechanisms break down in chronic disease and cell proliferation. identify targets for therapeutic intervention. ß Determine the bioavailability, safety, and efficacy of orally administered TFFs and other epithelial cell Objectives: growth factors in models of mucosal injury and ß Survey known sodium, chloride, SCFA, and inflammation. ammonia transporter expression in human colon ß Develop strategies for mimicking the enteric with comparison to murine models and evaluate antigen/TLR interactions to promote gut healing. segmental alterations in transporter expression on varied, defined fiber, and protein diets.

16 Research Goals are numbered for ease of reference only; the numbers do not indicate prioritization of scientific topics.

152 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Goals for Research

ß Understand the regulation of sodium-absorptive ß Compare colonic microflora before and after and chloride-secretory pathways during disease antibiotics in patients, with and without and identify targets for potential therapy of colonization by C. difficile, and use these data diarrheal disorders and non-immunosuppressive to develop a rational approach to reconstitute approaches to enhance repair. the microflora. ß Screen pediatric and adult U.S. populations for ß Conduct randomized, double-blind, controlled altered transporter complex expression and/or trials to manipulate the colonic microflora in gene mutations in congenital and acquired obesity as a possible adjunct therapy. constipation and diarrheal disorders, with the goal of developing individualized strategies for patients with chronic constipation or diarrhea. Research Goal 9.4: Establish the cause of diverticular disease and its complications, with modulation of disease. Research Goal 9.3: Determine the role of gut microflora in health and disease states of the colon. Diverticular disease and its complications can cause (See also Goals 1.20, 1.21, 3.1, and 5.3.) significant discomfort and reducedquality of life in many elderly individuals. Understanding the Microbes begin to colonize the digestive tract at risk factors for diverticulosis and its progression birth and seem to have important roles in normal to diverticulitis will enable researchers to develop physiology, including digestion, nutrition, and effective preventive strategies to reduce the burden immunity. Perturbations in the microflora have also of illness in this vulnerable population. For those been associated with various disease states. In some patients who develop complications of diverticular cases, overgrowth of a specific pathogenic bacterial disease, rigorous evaluation of medical and surgical species can cause disease, such as inflammation of options is needed to determine the most effective the colon in response to C. difficile infection. Other approach. conditions, like obesity or IBD, are associated with changes in the overall balance of different microbes. Objectives: Research to characterize the gut microflora will ß Identify risk factors for diverticular disease, generate new insights for therapeutic manipulation including genetics and lifestyle, and association of the microflora to maintain the health of the colon with complications (specificallydiverticulitis and reverse disease. and bleeding). ß Determine whether treatment with non- Objectives: absorbable antibiotics, mesalamine, prebiotics, ß Establish tissue banks of mucosal biopsies to probiotics, or other agents reduces the risk of allow large-scale, chip-based comparison of recurrent diverticulitis and is cost-effective. adherent bacteria on the surface epithelium ß Determine indications for surgery and the (biofilm) tobacteria in the normal microflora optimal surgical approach to complicated in feces. diverticular disease. ß Compare bacterial microflora inobese and lean ß Determine whether changes in lifestyle, especially humans using molecular fingerprint assays and diet, reduce the prevalence of diverticulosis sequence analysis of cloned 16S rDNA. and its complications (specifically, avoidance of specific dietary factors, such as and popcorn) and reduce the risk of diverticulitis.

Diseases of the Colon and Rectum 153 Goaloalss for for Rese Rarcesearchh

Research Goal 9.5: Understand mechanisms mechanism(s) of each of the conditions despite and develop tools for early diagnosis of colon commonly accepted theories, and little is known ischemia and angioectasia. about prevention strategies or the effectiveness of current therapeutic recommendations. Finally, new CI is the most frequent ischemic disorder of the GI treatment modalities have been developed in recent tract, yet it is very difficult to accurately diagnose. years; however, long-term outcomes and cost- No specific tests are available to diagnoseCI, except effectiveness information are not yet available. when infarction is present. Most episodes of CI resolve spontaneously and do not recur; however, Objectives: approximately 25 percent of patients present with ß Understand risk factors and preventive or develop irreversible disease requiring surgical strategies for anal disorders, including anal intervention, and approximately 5 percent develop fistulas and hemorrhoids, with appropriate a chronic colitis resembling ulcerative colitis or modification;natural history and impact Crohn’s disease that may worsen with the standard of obstetrical sphincter injury; medical and treatment for IBD. Identifying biomarkers for early neurological conditions; pelvic surgery; and the stage CI would allow earlier intervention and reduce role of surgical repair of sphincter defects. the rate of complications. ß Develop evidence-based algorithms for prevention, diagnosis, and treatment of perianal Objectives: fistulas (cryptoglandular and Crohn’s) and for ß Devise a means of diagnosing CI early (i.e., treatment of hemorrhoids. before infarction ensues) and of differentiating it ß Develop educational tools for providers and the from other disorders by developing biomarkers public to raise awareness of anorectal disorders, for this disease process. including perianal abscess and fistula, and ß Determine the underlying, proximate cause of hemorrhoids, with particular focus on accurate CI, especially with regard to the behavior of diagnosis, initial treatment, and prevention. colonic arteriolar and venular microvasculature, as well as the relationship of the bowel vasculature to serotonergic agents. Research Goal 9.7: Improve the understanding ß Determine why angioectasias develop and and management of fecal incontinence. (See also understand the potential mechanisms for Goal 2.2.) altered vasculature and blood flow. Fecal incontinence is an underreported and underappreciated condition frequently associated Research Goal 9.6: Improve management of with shame, embarrassment, and stigma. Because of anorectal disorders. these aspects, it has been difficult to identify persons affected, risk factors, biologic causes, and social Anorectal disorders are common clinical conditions, and environmental factors. Fecal incontinence has but limited basic science data exist about these a major impact on quality of life of individuals living disorders. While not life-threatening, the conditions at home and in nursing homes, impacting people may have a significant impact on a person’s quality of all ages, especially women and the elderly. New of life. The prevalence of these disorders is poorly treatment modalities and appropriate utilization studied, with the exception of fistulas in Crohn’s and acceptance of prevention and management disease and, recently, fecal incontinence. Limited strategies are needed. scientific information is available on the underlying

154 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Goals for Research

Objectives: ß Determine efficacy of pharmacologic agents in ß Develop generally accepted definitions of prevention of radiation injury via multicenter fecal incontinence with longitudinal studies trials with collaboration among experts in to identify risk factors, including medical gastroenterology, oncology, and radiation and surgical treatments that may cause oncology. Agents may have additional incontinence, and preventive strategies. applications for biodefense. ß Understand the existence and causes of ß Develop evidence-based algorithms for differences in the rate and impact of fecal prevention and treatment of radiation proctitis. incontinence in different groups. ß Investigate medical and surgical treatment modalities with development of improved Research Goal 9.9: Determine causes of measures and algorithms for treatment of fecal appendicitis and modulate the course of the disease. incontinence. ß Develop evidence-based strategies for the The onset of appendicitis is nearly always a , prevention, and management of emergency. Delays in diagnosis and treatment fecal incontinence, particularly in the aged and increase the likelihood that the organ will rupture residents of long-term care facilities. and disperse bacteria into the peritoneal cavity. The ß Understand the direct and indirect economic resulting peritonitis may contribute to complications, and societal impact of fecal incontinence such as abscess formation, wound infection, urinary and the potential benefits of prevention and tract disorders, small bowel obstruction, or even treatment interventions. death in a small minority of patients. Understanding ß Develop educational tools for providers and the the causes of appendicitis and ways to delay public to raise awareness of fecal incontinence. progression will help reduce the morbidity and mortality associated with this serious disease.

Research Goal 9.8: Reduce the frequency and Objectives: severity of radiation injury to the colon. ß Determine the effect of dietary factors, such as fiber content, prebiotics, probiotics, and bowel Radiation colitis—damage to the colon mucosa or function (constipation), on the incidence of vasculature due to radiotherapy for abdominal or appendicitis, especially in children. pelvic cancer—can manifest within weeks or even ß Determine the role of the immune-mediated years after radiation exposure. Researchers are response in the histopathology and clinical course looking for ways to precisely modulate radiation of appendicitis. dosage to maximize therapeutic effectiveness, while ß Identify high-risk patients from an immune simultaneously minimizing or eliminating radiation- standpoint and develop modifications of the related injury to healthy colon tissue. Algorithms to clinical approach to treatment of patients with accomplish this goal must allow for variation among different immune profiles. different types and stages of cancers, as well as ß Determine the role of antibiotic therapy other patient-specific characteristics. and other non-surgical approaches for the management of appendicitis. Objectives: ß Develop improved methods for early detection ß Determine prognostic factors (e.g., genetic of appendicitis. factors, co-morbidities) that are important in the development of chronic radiation injury.

Diseases of the Colon and Rectum 155 MAJOR CHALLENGES AND STEPS In addition, sensitive molecular techniques, TO ACHIEVE the RESEARCH GOALS such as PCR or microarrays, do not reliably distinguish between dead or non-viable Collaboration with industry: Collaboration organisms and organisms that are ingested with protein chemists and the biotechnology and simply passing through the gut compared and pharmaceutical industries to provide to microbes that are viable and capable of sufficient quantities of TFFs and other growth growth in the gut. The total metabolic activity factors would accelerate the testing of these (metabolome) of the microflora represents the factors in chronic preclinical studies and sum of thousands of species and, in theory, clinical intervention trials in human patients. could provide a less complex, quantitative approach to studying the microflora. New Research resources: Progress in the field technology development would facilitate would be aided by the establishment of measurement of the metabolome of the colonic centralized resources that would encourage microflora. Metabolomic techniques could sharing of biologic samples and patient be developed to study the human or animal data, as well as provide opportunities for microflora in vivo using noninvasive methods, collaborative research. A comprehensive such as breath analysis. The use of radioactive tissue bank could be created to collect, store, precursors of bacterial end-products, like and disseminate normal and diseased human ammonia or hydrogen, would allow for assays colonic specimens that are defined with respect of microbial metabolism. to anatomic segment and clinical data. The development of database capabilities and Given the expected complexity and diversity clinical consortia for randomized clinical of the microflora, the development of robust trials with standardized endpoints would databases and software tools to analyze large enable direct comparisons among clinical amounts of data from multiple laboratories research outcomes. The development of a would accelerate research across the field. The systems-based approach to the study of colonic Human Microbiome Project, which is being transport using a limited number of defined implemented through the NIH Roadmap for cultured cell and transgenic mouse models Medical Research, represents an important and comprehensive expertise in cell biology, step toward meeting these challenges by structural biology, transepithelial transport, providing a basic catalogue of the constituents nutrition, imaging, and computational of the stable microflora in all humans and modeling would generate a new perspective a description of variations in the microflora on the causes and treatments of colorectal that occur among individuals. The Human diseases. Microbiome Project will also facilitate the development of essential research tools Research tools for the microflora: The vast and resources. and complex gut microflora present several challenges to research on the physiology of the Clinical research: Diverticulosis is common colon and rectum in health and disease. For in Western countries, but infrequent in example, the microflora adherent to the colonic underdeveloped countries. Conducting mucosa—the “biofilm”—may be more relevant clinical research studies to compare different than the microflora in feces. Thus, research on populations would help to define the risk the microflora would benefit from the use of factors. Clearly defining symptomatic mucosal biopsies from colonoscopy rather than diverticular disease and distinguishing the traditional reliance on stool specimens. symptomatic diverticular disease from IBS is a

156 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases difficult, but important, challenge. Prevention Particularly for fecal incontinence, methods trials for diverticular disease will involve to overcome the reluctance of patients to follow-up for several years to detect significant discuss their symptoms and the reluctance of differences in outcomes. Similarly, intervention providers to inquire about these symptoms trials will also require long time periods, would improve opportunities for research and during which a method to control differences in treatment. Prevention trials would require diet among participants will be an important long time periods and be complex to manage. consideration. Central resources are especially important for diseases that are difficult to Research on appendicitis is limited by study in a single center with limited access difficulties in developing a network to study to patients, such as radiation colitis, which this condition in a pediatric population with generally affects an elderly population with an acute, self-limited disorder. Innovative multiple medical issues. approaches to research collaboration would promote progress on appendicitis. In addition, The frequency of anorectal disorders new methods are needed to obtain accurate and interface of patients with multiple dietary histories in patients, including children. providers makes it difficult to develop an effective system of data collection for these Animal models: Research progress could be conditions. Moreover, anal disorders often stimulated by encouraging the development occur concomitantly, which complicates the of novel animal models that faithfully mimic evaluation of treatment outcomes. The field colonic and rectal disorders in human patients, would benefit from broader understanding of such as diverticular disease and radiation colitis. the variety of anorectal disorders, the typical symptoms, and the criteria for diagnosis.

Diseases of the Colon and Rectum 157 Proposed roles of pancreatic enzymes and other factors in normal pancreatic function compared to the pathogenesis of pancreatitis.

Image courtesy of Dr. Heiko Witt. Reprinted from Gastroenterology, 132,Witt H, Apte MV, Keim V, Wilson JS. Chronic pancreatitis: challenges and advances in pathogenesis, genetics, diagnosis, and therapy, pp. 1557-1573, Copyright 2007, with permission from Elsevier.

 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Diseases of the Pancreas

SUMMARY OF RESEARCH GOALS

The exocrine pancreas, which produces and secretes multiple enzymes necessary for digestive function, is vulnerable to a variety of disorders that, collectively, affect more than 1 million Americans each year.

The Commission recommends a series of research goals that are focused on the most prevalent of these disorders—acute and chronic pancreatitis and their sequelae. Pancreatitis can be triggered by many possible causes, including gallstones, alcohol abuse, certain medications, autoimmunity, and diseases such as cystic fibrosis (CF), or it may be of unknown etiology. Research is needed to identify the biologic and genetic factors that increase a person’s susceptibility to and/or the transition to chronic disease. The development of innovative diagnostic, preventive, and therapeutic approaches to pancreatitis has the potential to reduce the burden of this disease in both children and adults. Equally important is the need to understand the mechanisms of pancreatic pain, a highly prevalent complication of all forms of pancreatitis that is difficult to treat and severely erodes the quality of life of patients with . Research to understand the risk factors for and mechanisms of progression to pancreatic cancer is particularly critical for patients who develop pancreatitis at a young age and are, therefore, at a corresponding increased lifetime risk for pancreatic cancer.

Diseases of the Pancreas 159 INTRODUCTION AND BACKGROUND The most frequent known cause of chronic pancreatitis is also chronic alcohol abuse. The pancreas plays a very important role in Additional causes include hereditary nutrient absorption via its synthesis of digestive pancreatitis due to mutations in genes that enzymes (e.g., , phosphatases, , encode for key pancreatic molecules, such as , and others). The can be or the cystic fibrosis transmembrane afflicted by a surprising diversity of pathologic conductance regulator (CFTR), abnormalities processes leading to various diseases and clinical of which are associated with CF and its syndromes. Disorders of the pancreas affect variations. In up to 10-20 percent of cases, the more than 1 million persons in this country cause remains unknown (idiopathic). The most (1.15 million in 1998) and are estimated to frequent sequelae of chronic pancreatitis are result in nearly $3 billion in annual direct and pain, endocrine failure (resulting in diabetes indirect costs. As a group, there were 277,000 mellitus), and exocrine failure (resulting in fat hospitalizations and 475,000 ambulatory and protein malabsorption). Pain is present care visits due to pancreatic diseases in 2004. in approximately 75 percent of patients with Specifically, acutepancreatitis is the commonest alcoholic chronic pancreatitis, 50 percent of cause of hospitalization for pancreas-related patients with late-onset idiopathic chronic disorders in the country, accounting for 254,000 pancreatitis, and all patients with early-onset discharges, with a median charge of $13,435, idiopathic chronic pancreatitis. Pain is the most and resulting in more than 2,800 deaths in 2004. difficult symptom of chronicpancreatitis to CF, which interferes with pancreas function, treat, with many patients facing the prospect is the most common inherited fatal disease in of lifelong dependence on narcotics. Our lack Caucasians, occurring in about 1 in every 3,500 of knowledge about what causes pain in births each year. This burden of disease contrasts pancreatitis has been a serious obstacle to with the relatively sparse number of researchers improving the care of these patients, leading and actively funded proposals in this area. to various empiric approaches that are often based on purely anatomical grounds, are The most widespread disorders of the generally highly invasive, and are not always pancreas are acute and chronic pancreatitis, effective. Individuals with alcoholic pancreatitis or inflammation of thepancreas. In acute also suffer from issues of addiction to alcohol, pancreatitis, inflammation begins abruptly smoking, and narcotics, which considerably and either resolves or worsens within days. complicate the care of these patients. Finally, About 2 percent of acute pancreatitis cases chronic pancreatitis is associated with an are fatal, often due to complications affecting increased risk for pancreatic cancer. While other organs, such as the , cardiovascular relatively uncommon, development of system, or kidneys. The most common causes pancreatic cancer can be particularly important of acute pancreatitis are gallstones, which in those whose disease begins in childhood, such traverse the and may inflame the as patients with . pancreas by transiently blocking its drainage into the , and alcohol excess. Other With increased use of sophisticated abdominal causes include metabolic derangements, imaging procedures, such as high-resolution such as increased circulating , CT scan and MRI, cystic lesions of the certain medications, and invasive diagnostic pancreas are being recognized, often as tests evaluating the pancreas and bile incidental findings during investigation ducts (e.g., endoscopic retrograde cholangio- for other abdominal complaints. Some of pancreatography [ERCP]). these (pseudocysts) occur in the setting of

160 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases pancreatitis and may be a consequence of variations in the gene encoding CFTR will have ductal injury. In the absence of preceding residual pancreatic exocrine function, but may inflammation, these lesions are ominous be at risk for recurrent pancreatitis. and often neoplastic in nature. In recent years, advances in the understanding of the Although diabetes can be considered a disorder pathology of these cystic lesions have led to of the pancreas, it is not considered a digestive revision of the classification and nomenclature disease in the strict sense and, although an of these tumors into mucinous cystic neoplasm important component of chronic pancreatitis (MCN) and intraductal papillary mucinous and pancreatic cancer, will not be discussed neoplasm (IPMN) and its variants. Both MCN in this research plan. Pancreatic cancer, the and IPMN are mucinous tumors that have fourth leading cause of cancer death in the U.S., potential to turn malignant. While MCNs are is included in the chapter on Cancers of the frequently found in middle-aged women, IPMN Digestive System. is often seen in the elderly. Since mucinous tumors of the pancreas are precancerous, their discovery is an important health concern. Recent RESEARCH ADVANCES They present great challenges with regard to diagnosis, treatment, and surveillance. Acute pancreatitis

From a pathologic perspective, three distinct Researchers have recognized clearly that acute precursors to invasive pancreatic cancer have pancreatitis can affect the entire body and been identified, including: (1) MCNs, (2) IPMNs, is associated with a systemic inflammatory and (3) pancreatic intraepithelial neoplasia response. Organ failure has been found to be (PanIN). The first two are macroscopic (i.e., a more important determinant of morbidity generally visible on imaging techniques), while and mortality than necrosis or other local the third is microscopic in nature. All three complications. Other important advances that pre-malignant processes begin as benign, are still in progress include elucidation of the noninvasive entities and progress through complex cytokine/chemokine responses in acute a series of as-yet poorly defined genetic and pancreatitis, the development of in vivo models pathologic changes toward cancer. The link of acute pancreatitis, and understanding the between chronic pancreatitis and pancreatic nature of calcium and other cell signaling cancer and the role of PanINs in these diseases processes that mediate the physiologic and are incompletely understood. pathologic acinar cell responses.

The product of the CF gene, CFTR, is important Chronic pancreatitis for chloride ion transport on the apical surface of epithelial cells. Mutations in Progress has been made in understanding CFTR result in abnormally thick secretions fibrosis events in thepancreas, particularly that damage a variety of organs, including the with regard to the role of stellate cells. With lungs, liver, and pancreas. Pancreatic exocrine the development of valid animal models to failure occurs in 85-90 percent of CF patients study pancreatic pain, important molecular and results from blockade of ducts by thick mechanisms and potential therapeutic targets, mucus plugs, causing injury and fibrosis. Less such as receptors and ion channels on sensory frequently, diabetes will also result. In addition neurons (e.g., TRPV1), are beginning to to the classic form of CF, patients with milder be identified.

Diseases of the Pancreas 161 Genetic mutations and the risk Pancreatic imaging of pancreatitis Advances in endoscopic ultrasound (EUS) Only a small subset (usually less than 5 technology have improved dramatically the percent) of patients with known risk factors ability to visualize even subtle alterations for pancreatitis (e.g., chronic alcohol abuse in pancreatic structure. These changes are or ) develops the disease. visible before traditional cross-sectional However, the genetic basis for this is not imaging techniques (e.g., CT scan) show understood. Since the discovery in 1996 that any abnormality, allowing for the possibility mutations in the cationic gene of diagnosing chronic pancreatitis early. cause hereditary pancreatitis, other genes However, the capability for high-resolution have been implicated in apparently sporadic imaging is also the greatest drawback of this pancreatitis, such as recent reports concerning technology. Subtle alterations in structure the role of genetic variation in the trypsin- are seen, for example, in alcoholics without degrading enzyme, chymotrypsin C. The pancreatitis, smokers, the elderly, and after frequent identification of mutations in the bouts of acute pancreatitis. EUS also provides CFTR gene and the serine protease inhibitor, the opportunity to obtain tissue for histologic Kazal type 1 (SPINK1) gene in patients with diagnosis of chronic pancreatitis without idiopathic chronic pancreatitis and in a small surgical resection of the pancreas. proportion of the healthy population suggests that genetic predisposition may be necessary Cystic lesions of the pancreas for development of disease in those with identifiablerisk factors. A major boost to the field has come from the World Health Organization classification of Recognition of autoimmune pancreatitis cystic disorders of the pancreas, which has (AIP) as a distinct clinical entity distilled many different types of classifications into one that determines whether or not the AIP is the pancreatic manifestation of a cells are malignant and whether or not tissue systemic autoimmune disorder. AIP is a form invasion has occurred. This revised system of chronic pancreatitis distinct from classically has significantly improved the ability of described chronic, calcifying pancreatitis. AIP researchers to coordinate multiple studies. has unique clinical, serologic, morphologic, Progress in our understanding of cystic and histologic features. The most frequently lesions of the pancreas has come from the described presentation of AIP is that of a identification of differences in diagnosis and pancreatic mass that mimics pancreatic ductal natural history of MCN from IPMN, as well adenocarcinoma in clinical presentation. If as the recognition that not all forms of IPMN recognized prospectively, the inflammatory require operative intervention. In addition, mass of AIP responds to steroid therapy, studies have introduced the concept of less and the need for pancreatic surgery can be aggressive treatment for small (less than avoided. Interestingly, unlike usual chronic 3 cm) cystic lesions in the pancreas. Finally, pancreatitis, AIP is a relatively painless disease researchers have gained important new despite histology showing chronic pancreatic insights into the molecular mechanisms of inflammation and evidence of pancreatic edema, neoplastic transformation of cystic lesions. peripancreatic inflammation, and, in some cases, pancreatic calculi. This phenomenon is highly worthy of further study.

162 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases GOALS FOR RESEARCH 17

Research Goal 10.1: Determine the biologic Significant insight has been gained into the factors involved in the pathogenesis of acute mechanisms by which alcohol or other insults pancreatitis, with particular emphasis on the lead to acute cellular injury. However, how these mechanisms of tissue necrosis and systemic events lead to chronic inflammation andfibrosis or complications. endocrine and exocrine cell loss remains unknown. These questions are of great clinical relevance given It is unclear why the majority of patients with how often chronic pancreatitis is accompanied by acute pancreatitis do not develop the systemic enzyme insufficiency leading tomalabsorption and inflammatory response syndrome or pancreatic insulin deficiency leading todiabetes. necrosis. However, those who do will have a perilous clinical course, often complicated by Objectives: organ failure and death. It is critical, therefore, ß Understand how , smoking, and other to understand the biologic pathways leading putative etiologic factors contribute to chronic to necrosis following a noxious insult. Such injury. knowledge has the potential to identify novel ß Determine the biology of pancreatic fibrosis and and effective therapeutic targets, as well as much chronic injury, including the role of stellate cells needed surrogate markers (clinical, hematological, and other co-factors. or imaging) for mortality, necrosis, and systemic ß Understand the nature and mechanism of complications in acute pancreatitis. endocrine cell loss in chronic pancreatitis. ß Understand the mechanisms of parenchymal and Objectives: islet cell regeneration in response to chronic injury. ß Understand how noxious insults, such as ethanol, ß Understand the biologic nature and importance of gallstones, and others, initiate pancreatic injury islet-parenchymal communication in the pancreas. and inflammation in adults and children. ß Understand the role of obesity, dysfunction, and anatomic variations of the Research Goal 10.3: Understand genetic pancreas in the development of pancreatitis. factors and their interactions with exogenous ß Identify the biologic mechanisms leading to insults, with respect to pathogenesis, complications, necrosis in acute pancreatitis. and natural history of pancreatitis and other ß Understand the biologic mechanisms responsible pancreatic disorders. for post-ERCP pancreatitis. ß Understand the role of specific cytokines and other It is clear that host factors, including genetic inflammatory factors, including entericbacteria variability, have a major influence in determining and their products, in the development of systemic the risk for inflammation and subsequent clinical complications and multi-organ failure. phenotype after insults, such as excessive alcohol use. Knowledge of these specific factors will be valuable in risk stratification and development of Research Goal 10.2: Understand the transition effective measures for prevention of disease. In from acute to chronic pancreatic injury, particularly addition, identification of these genes will provide with respect to the role of alcohol. crucial insight into the molecular mechanisms underlying pancreatitis and its complications.

17 Research Goals are numbered for ease of reference only; the numbers do not indicate prioritization of scientific topics.

Diseases of the Pancreas 163 Goaloalss for for Rese Rarcesearchh

Objectives: ß Optimize nutritional strategies for the treatment ß Understand genetic factors that predispose to of acute pancreatitis and its complications. increased risk or severity of acute pancreatitis. ß Understand the effect of endoscopic approaches ß Understand the role of genetic factors that (e.g., stents, stone removal, and stricture predispose to chronic injury and/or impaired formation), surgery, and radiologic interventions recovery from acute insults. for the treatment of organized necrosis, ß Understand gene-environment interactions pseudocysts, pain, and other complications of in the development of benign and cystic acute and chronic pancreatitis. neoplasms, as well as pancreatic cancer arising ß Develop novel pharmacologic approaches for in the context of chronic pancreatitis. the reversal of fibrosis and prevention of islet ß Understand the genetic factors that predispose and parenchymal cell loss, including islet cell and to sensitization and pain in the setting of stem cell transplant strategies. pancreatic injury. ß Understand the role of immunosuppressive ß Develop novel models of pancreatic disease therapy for the treatment of autoimmune derived from targeting of specific genes. pancreatitis.

Research Goal 10.4: Develop and validate Research Goal 10.5: Understand the therapeutic interventions for treatment and/or neurobiology of the pancreas with respect to progression of pancreatitis and its complications. mechanisms of pain and neurogenic inflammation.

Much progress has been made in elucidating the Pain is the major symptom that drives patients signaling mechanisms of inflammation and fibrosis to seek health care in a variety of pancreatic in other disease models, and several cytokines and disorders, including chronic pancreatitis and other molecules have been identified as major pancreatic cancer. An understanding of how these players in pathogenesis. Synthetic agents directed disorders affect the sensory nerves conveying against these targets are becoming increasingly pain from the pancreas is, therefore, important for available, and their effectiveness in modulating effective therapies to be developed. Further, recent the acute and chronic inflammatory responses in investigations have suggested that communication the pancreas needs to be determined. In addition between the pancreas and its nerves is bi- to drugs, endoscopic (e.g., placement of stents) directional and that neurogenic influences can and surgical approaches also hold promise, and modify inflammation and perhaps influence the their role in the management of acute and chronic behavior of cancerous cells. pancreatitis needs to be examined rigorously through carefully conducted prospective studies. Objectives: ß Understand the biologic basis and mechanisms Objectives: responsible for peripheral sensitization in chronic ß Understand the effects of specific pancreatitis. pharmacologic therapies, including anti- ß Understand changes in central sensitization and cytokine agents for the treatment of acute the underlying mechanisms in patients with pancreatitis, as well as the prevention and painful chronic pancreatitis. treatment of necrosis and multi-organ failure. ß Understand the biologic basis of narcotic ß Develop novel and more effective dependence and resistance in patients with pharmacologic and/or endoscopic approaches chronic pancreatitis. to prevent ERCP-induced pancreatitis.

164 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Goals for Research

ß Identify novel therapeutic targets for more Research Goal 10.7: Develop more accurate effective analgesic therapy. and useful approaches to the diagnosis of chronic ß Understand the mechanisms by which pancreatitis by functional, radiologic, endoscopic, autonomic, spinal, and neurohormonal factors or pathologic/cytologic means. influence the course of acute and chronic pancreatitis and their complications. Innovative strategies are needed for the detection of chronic pancreatitis to enable early diagnosis, predict and monitor disease activity and Research Goal 10.6: Define theepidemiology progression, and distinguish etiopathologic subsets, and clinical course of acute and chronic pancreatitis, such as autoimmune or genetic pancreatitis. The including alcoholic pancreatitis, autoimmune pancreas is a relatively small and inaccessible organ. pancreatitis, and cystic fibrosis, through population- Direct means of evaluating pathologic changes are based studies in adults and children. invasive and carry substantial risk. Most clinical information, therefore, is obtained by indirect Progress in this area has been hampered by the means, including biochemical and radiological tests. lack of standardized approaches to diagnosis and Research on alternative and/or more accurate tests classification and the fact that no single center sees of form and function will be very important for enough cases to permit robust and generalizable future clinical progress in pancreatology. conclusions. Expanding our knowledge of these issues is critical in order to develop effective Objectives: estimates of the burden of disease and formulate ß Develop and validate unequivocal criteria for guidelines for screening, prevention, and treatment. diagnosis of chronic pancreatitis (histologic and This gap in knowledge is particularly significant for non-histologic) and distinguish etiopathologic the pediatric population. subsets, such as autoimmune or genetic pancreatitis. Objectives: ß Develop novel methods, including minimally ß Identify reliable prognostic factors of severity invasive biopsy techniques, to help identify of acute pancreatitis at admission that can be patients with early chronic pancreatitis and utilized to stratify patients who can be enrolled distinguish etiopathologic subsets. in studies to evaluate new therapies. ß Develop and validate novel and less invasive ß Understand the co-factors necessary for methods to recognize and monitor fibrosis. development of fibrosis in patients with ß Develop and validate more accurate and recurrent pancreatitis and the rate of disease convenient tests to assess and monitor progression in chronic pancreatitis. pancreatic function. ß Understand the natural history of disease in ß Develop and validate reliable noninvasive patients with chronic pancreatitis due to various methods for the diagnosis and monitoring of etiologies, including autoimmune pancreatitis. autoimmune pancreatitis. ß Understand demographic, ethnic, genetic, and environmental factors that elevate the risk of disease development and rate of disease Research Goal 10.8: Define the role of progression. pathologic lesions, such as pancreatic intraepithelial ß Develop and validate reliable measures of neoplasms, and other factors that may correlate pain and quality of life in patients with chronic with the risk of malignant transformation in chronic pancreatitis in adults and children. pancreatitis and cystic neoplasms and map their morphologic and molecular progression.

Diseases of the Pancreas 165 GOALS FOR RESEARCH

In a small but important subset of patients, Objectives: pancreatic cancer develops in the setting of a ß Understand the epidemiology and natural history cystic lesion or chronic pancreatitis. The biologic of cystic disorders of the pancreas and correlate mechanisms underlying this risk remain unknown, the findings with the results ofimaging and fluid but further knowledge in this area may offer the analysis. potential for developing effective methods of ß Identify biomarkers in cystic fluid and tissue surveillance and prevention, including the use aspirates for providing unequivocal diagnoses of adjuvant/neoadjuvant therapy after partial and pathologic distinction. resection. This may be particularly important in ß Understand the role of invasive and noninvasive patients with hereditary pancreatitis who are methods for surveillance of patients at risk for often very young at the onset of their disease and malignancy. accumulate risk for cancer throughout their life. ß Understand the clinico-pathologic correlations Other subsets that may benefit include patients involving PanINs, small cystic lesions, and IPMN. with IPMN, in whom large segments of the ß Understand the genetic and morphologic pancreatic epithelium are vulnerable to progression between precursor lesions and cancerous change. pancreatic cancer, particularly in the context of chronic pancreatitis.

MAJOR CHALLENGES AND STEPS through a comprehensive national database of TO ACHIEVE the RESEARCH GOALS acute pancreatitis. Such a database could be used to define mortality and morbidity and to Standards for diagnosis: Differences in the develop reliable prognostic factors of severity diagnosis and care of patients with pancreatic at admission, which would enable stratification disease impede efforts to compare data across of patients for enrollment in clinical trials to centers or clinical trials. The field would evaluate new therapies. Similarly, a widely benefit from the development of consensus accessible patient registry and a repository guidelines for diagnosis of chronic pancreatitis, of biologic samples for banking tissue, serum, including histologic and clinical criteria. In and DNA could increase research on the addition, validation of reliable tools to measure basic mechanisms of onset and progression pain and quality of life in patients with chronic of pancreatic diseases. Establishing pancreatitis would improve patient care and multicenter consortia for the study of chronic enhance research efforts. pancreatitis in adults and children would provide opportunities for collaboration among National resources for pancreas research: researchers with complementary expertise. A significant obstacle to research progress on pancreas diseases is that relatively few Animal models: Development and validation patients are treated at any single center. of animal models of both acute and chronic Research could be accelerated by pooling data pancreatitis (alcoholic and non-alcoholic) and and biosamples and making these resources its complications would accelerate progress on available to investigators across the U.S. understanding risk factors for this disease.

166 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Alignment of research and clinical investigators, clinicians, and clinical forces: The rapid development of endoscopic investigators with different areas of expertise. and other relatively noninvasive approaches A concerted effort to align these forces will be to visualizing the pancreas provides new important in maximizing the efficiency and opportunities for building multidisciplinary productivity of research efforts. research teams that include laboratory

Diseases of the Pancreas 167 Illustration of the life cycle of the hepatitis B virus in . Knowledge of how hepatitis B infects the liver has aided the development of many new treatments for this disease.

Image courtesy of Dr. Edward Doo, reprinted from the Management of Chronic Hepatitis B: 2006 conference, April 2006 (http://www.niddk.nih.gov/fund/other/hbv2006/index.htm).

 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Diseases of the Liver and Biliary System

SUMMARY OF RESEARCH GOALS

Major research goals relating to diseases of the liver and biliary system were set forth in the trans-

NIH Action Plan for Liver Disease Research, which was released in 2004. Taking that effort into consideration, the Commission proposes research goals that are intended to complement and reinforce the comprehensive recommendations made in the Action Plan. Understanding normal liver and biliary function and development will provide a solid foundation for new approaches to detect, prevent, and treat liver and biliary diseases. Although the burden of some forms of viral hepatitis has decreased in recent years due to efforts such as the development of vaccines and antiviral therapies, more work is needed to find safe, effective means for prevention and treatment of all forms of acute and chronic viral hepatitis, as well as human immunodeficiency virus (HIV)-associated liver disease. Hepatic steatosis (fatty liver disease) is an increasingly common form of liver disease in the U.S. Research to discover the basic mechanisms underlying steatosis will point to new therapeutic strategies. Similarly, research is needed to uncover the genetic bases and fundamental cellular mechanisms of a range of disorders, including drug- induced liver disease, autoimmune diseases of the liver, childhood syndromes and other hereditary liver diseases, cirrhosis, liver cancers, and gallstones. More knowledge of all of these conditions will accelerate the search for new means of prevention, diagnosis, and treatment, such as improved procedures for liver transplantation, to reduce the burden of liver and biliary diseases in the U.S.

Diseases of the Liver and Biliary System 169 INTRODUCTION AND BACKGROUND mechanisms by which acetaminophen injures the liver and how aspirin, when given to Diseases of the liver and biliary system are children during viral illnesses, can lead to major causes of illness and death worldwide fatal liver injury; (6) development of means and in the U.S. These diseases encompass of early detection of liver cancer at a point a wide range of conditions, from viral when resection or liver transplantation can hepatitis to gallstones, , prevent spread and prolong life; and (7) fatty liver disease, autoimmune liver and improved means of diagnosis and management biliary conditions, inherited and congenital of gallstones and evolution of laparoscopic disorders, liver conditions caused by toxins or surgery for (removal of the medications, and liver and bile duct cancer. gallbladder). Collectively, diseases of the liver and biliary system rank in the top ten causes of death These advances have all been the result of and accounted for over 55,000 deaths in 2004 progress in medical research on liver and (~2.5 percent of all deaths). Importantly, biliary disease and have had a material effect the majority of liver and biliary diseases on the frequency (incidence and prevalence) can be accurately and easily diagnosed, and and impact (mortality and morbidity) of liver specific therapies are available for most. This disease. Rates of death from cirrhosis and optimistic assessment, however, is a recent end-stage liver disease have been steadily change. Fifty years ago, most causes of liver declining in the last 15 years and are at an all- disease were unknown, diagnosis was difficult, time low. Rates of acute hepatitis A, B, and C and only one or two rare conditions were have declined by more than 80 percent in the treatable. This dramatic change in the last 50 last 20 years, and these diseases are now at years has been brought about by significant historically low levels. advances in our understanding of the liver and its diseases followed by inroads into means of The changes in understanding and ability to prevention and cure. diagnose, prevent, and treat liver disease in the last 25 to 50 years have been profound. Examples of important breakthroughs However, the burden of liver disease in the include: (1) discovery of the hepatitis B virus U.S. remains an important problem. Deaths in 1964, followed by development of means from liver and biliary disease account for for its detection, prevention, and treatment; approximately 2.5 percent of all deaths and (2) discovery of the hepatitis A virus in 1974 have remained constant at approximately with subsequent development of means for 55,000 per year for the last 10 years. Over diagnosis and an effective hepatitis A vaccine; the last decade, liver cancer incidence has (3) discovery of the virus in 1989, increased in the U.S. at a rate second only followed rapidly by means for its detection, to that of adenocarcinoma of the esophagus. prevention of its spread by , Hepatitis C remains a major cause of end- and steady improvement in treatment; stage liver disease and takes an increasing toll (4) development of liver transplantation on medical resources. Pediatric liver disease, over the period of 1963 to 1983 with its although rare, remains largely untreatable subsequent acceptance as the standard except with liver transplantation. of care for management of end-stage liver disease remains common, and surgery for disease and liver cancer; (5) improvements gallstones is still a major health cost in the in understanding how medications can U.S. With the burgeoning epidemic of obesity cause serious liver disease, including the throughout the world, non-alcoholic fatty liver

170 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases disease is emerging as an important new cause total of 214 research goals in 16 categorical of significant liver disease. areas of research. The National Commission for Digestive Diseases, in recognizing the These factors are the basis for a call to major contribution of that plan and its promote further research on liver and biliary updates, made extensive use of the Action Plan tract structure, function, and disease. Given as a foundation to synthesize and update goals the recent dramatic advances in genetics and for research in liver and biliary diseases for genomics research, with the completion of this research plan. This chapter extensively the Human Genome Project and with very cross-references the goals of the Action Plan, substantial advances in cell and molecular and the two documents are intended to be biology, the promise of research directed at used in a complementary fashion by those specific liver conditions is all the greater. interested in advancing liver and biliary disease research. The cross-referenced goal in The preparation of this chapter was greatly the Action Plan is provided after the listing aided by the availability of the 2004 of each research objective in this document comprehensive plan for research in liver (by Action Plan chapter and goal number). and biliary diseases, the trans-NIH Action In addition, the structure of this chapter, Plan for Liver Disease Research including the alignment of recent research (http://liverplan.niddk.nih.gov). Developed by advances with individual research goals, is a series of 16 working groups of researchers, meant to optimize cross-referencing with the academicians, and lay persons involved in liver Action Plan and is not an indication of priority disease research, the Action Plan proposed a of scientific topics.

Goals for Research

Molecular and Cell Biology of for feedback control of cholesterol synthesis and the Liver and Biliary System uptake by hepatocytes; this control is mediated by (Action Plan Chapter 1) sterol-regulatory element binding proteins (SREBPs) in the (ER). In the presence Recent Research Advance of low levels of cholesterol, SREBPs move to the Golgi and release a transcription factor portion that Progress in defining molecular pathways controlling up-regulates cholesterol synthetic and transporter liver and biliary cells. There are numerous recent pathways, but in the presence of high levels of examples of continuing progress in defining the cholesterol, SREBPs are bound to Scap and Insig- molecular pathways that control liver and biliary 1 and retained in the ER, resulting in decreased cell function. Two striking advances, one on transcription of target genes. polarity and another on regulation of cholesterol synthesis, are described here. Radixin is a major hepatocyte protein that has been shown Research Goal 11.1: Define the molecules, to tether proteins such as MRP2 to the canalicular processes, and pathways that underlie normal membrane; siRNA suppression of radixin results liver cell function, which can then be applied to in loss of polarity, structure, and function of apical understanding the cellular and molecular basis of hepatocyte membranes. Studies in cell culture have disease processes. further strengthened the “convergent mechanism”

Diseases of the Liver and Biliary System 171 Goaloalss for for Rese Rarcesearchh

The liver is the largest solid organ in the body Liver Cell Injury, Inflammation, and serves essential functions in regulating Fibrosis, and Repair (Action Plan metabolism and homeostasis. The major cell of Chapter 2) the liver is the hepatocyte, one of the body’s most versatile cells, which serves to produce proteins, Recent Research Advance , and complex carbohydrates, as well as to regulate energy balance, glucose and cholesterol Mechanisms of fibrosis. An important research metabolism, and to excrete foreign substances advance has been the recognition that activation and breakdown products of metabolism, drugs, or of hepatic stellate cells is a major factor in hepatic toxins by excreting them directly into the bile or fibrosis. Further dissection of the pathways and converting them to forms that can be excreted in cells involved in this process may provide the basis the urine. No single test can measure the overall for therapeutic interventions to prevent or reverse function of the liver and its hepatocytes, and the fibrosis in the liver. full range of their activity has yet to be completely described. Research on molecular and cell biology of the liver and biliary system is essential to Research Goal 11.2: Understand the cellular understanding the functions of the liver, how mechanisms of liver injury, inflammation, repair, and they are altered in disease, and how they can be fibrosis and develop effective means for monitoring corrected or improved. and treating diseases caused by these processes.

Objectives: Tissue injury and inflammation, repair, and fibrosis ß Define how molecules are transported across are fundamental components of all forms of acute membranes and to specific sites in theliver cell and chronic liver diseases. Understanding the (cell trafficking). (Chapter 1: A3, C1) mechanisms of liver cell injury and the resulting ß Fully understand the signaling mechanisms inflammation, fibrosis, and repair will help to develop that control the activity of liver cells (signal ways of preventing liver injury and reversing its transduction) and how these signaling effects. Liver cells die in response to inflammation or mechanisms interact. (Chapter 1: A1) immune attack in an orderly, predetermined fashion, ß Elucidate the steps of regulation of cholesterol and known as programmed cell death (apoptosis). The lipid synthesis, transport, and excretion. cellular pathways involved in apoptosis are complex, (Chapter 1: A2) but their delineation would help in developing ß Develop a comprehensive knowledge base of the means to treat virtually all liver diseases. Liver cell normal liver proteome, comprising an analysis of injury is usually accompanied by inflammation and the proteins in the hepatocytes, their amino acid immune reactivity. Cell injury, particularly if severe sequences, carbohydrate and lipid modifications, and accompanied by inflammation, can lead to secondary and tertiary structure, interactions, and abnormal healing and progressive hepatic fibrosis. functions. A better understanding of the normal Understanding fibrosis and the processes that lead to liver proteome would advance all components cirrhosis, including how to detect fibrosis in its early of knowledge about the liver and its functioning. stages, are major goals for research in this area. (Chapter 1: C3)

172 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Goals for Research

Objectives: The liver has a marked ability to regenerate. ß Delineate the steps in the process of hepatocyte Resection of half of the human liver is followed apoptosis. (Chapter 2: A2a) within 2-4 weeks by full restoration of the liver ß Understand how liver cells produce and respond structure, size, and function. The process of to inflammatory mediators and cytotoxic regeneration recapitulates, in many respects, the signaling mechanisms. (Chapter 2: A1a, B1) development of the liver in utero. Understanding ß Develop better small animal models for liver cell the developmental biology of the liver, how injury, inflammation, repair, andfibrosis. (Chapter embryonic stem cells differentiate into mature 2: C1) and functional hepatocytes and cholangiocytes, ß Develop noninvasive means of assessing liver and what processes and cellular signals initiate, injury and fibrosis. (Chapter 2: A3; Chapter promote, and conclude regeneration would aid 16: C1b) understanding of liver disease and how the liver ß Translate findings about cellinjury, inflammation, recovers from cell injury. Identifying signals that repair, and fibrosis to clinical diseases. Identify promote regeneration may well lead to therapies small molecules that might alter these processes that would aid in recovery from liver injury or and form the basis for translational research. surgery. Such research is also likely to help identify (Chapter 2: B3, C2a, C3) biomarkers for regeneration and for failure of regeneration in situations such as or liver transplantation. Developmental Biology and Regeneration of the Liver Objectives: (Action Plan Chapter 3) ß Define the cellular and molecular events that underlie liver development and what processes Recent Research Advance are shared with liver regeneration. (Chapter 3: A1b, B3). Identification and characterization of hepatic ß Identify and characterize the stem cells of the stem cells in fetal and adult liver. Multipotent liver and determine how to use such cells in progenitor cells have been isolated from human gene transfer and transplant studies to correct fetal liver that can differentiate into hepatocytes genetic mutations that lead to inherited and cholangiocytes. In mice, embryonic stem diseases, such as hemophilia, porphyria, cells can be induced to differentiate into hepatic alpha-1-antitrypsin deficiency,Crigler-Najjar lineages and can contribute to hepatic repair when syndrome, and other devastating diseases. transplanted into immune-deficient mice. (Chapter 3: A1a, C3a). ß Improve gene transfer techniques, gene transfer vectors, and means of supporting cell viability as Research Goal 11.3: Define the molecular and they are directed to home to the liver (Chapter cellular mechanisms underlying liver development 3: B1a, C1). and regeneration in health and disease and apply these findings to developing improved therapies for liver disease.

Diseases of the Liver and Biliary System 173 Goaloalss for for Rese Rarcesearchh

Bile, , and Understanding the processes that lead to bile (Action Plan Chapter 4) formation and excretion will provide necessary insights into diseases of the liver and how to Recent Research Advance correct them. Regulation of these pathways in health and disease might well improve liver Identification of physical and molecular regulators function and aid in recovery from liver injury. of bile flow. Cilia on cholangiocytes have been Furthermore, mutations in the genes that regulate shown to respond to bile flow and induce increases the steps in bile and cholesterol metabolism in intracellular calcium and decreases in cyclic AMP account for several severe forms of inherited liver mediated through flow receptors (polycystin-1), disease that might be alleviated by altering these calcium channels (polycystin-2), and adenylyl cyclase pathways using small molecules or gene therapy. on the cilia, providing a new model for regulation of ductal bile secretion. Fibroblast growth factor (FGF)- Objectives: 15 has been identified as playing an important role in ß Fully define the normal physiology and gallbladder filling. FGF-15 is induced in the terminal regulation of bile formation, including ileum as a result of bile acid signaling through cholesterol synthesis and catabolism. (Chapter the farnesoid X receptor (FXR) and circulates in a 4: B2a, B2b) hormonal fashion to the liver and gallbladder where ß Understand the pathophysiology of acquired it leads to gallbladder filling by acting on cyclic AMP- forms of cholestatic liver disease, which linked receptors on biliary smooth muscle cells. Thus, disturbed processes account for the retention of intra- and inter-cellular signals coordinate to control bile, and how to alleviate the consequences of gallbladder filling and emptying. bile retention. (Chapter 4: A2, C1, C2)

Research Goal 11.4: Delineate the normal Viral Hepatitis pathways of uptake, metabolism, and secretion (Action Plan Chapter 5) of bile salts, bilirubin, and other biliary lipids and solutes; characterize the alterations in these Recent Research Advances pathways that participate in the pathogenesis of liver diseases; and develop means for diagnosis, New treatments for hepatitis B. In the past 5 treatment, and prevention of cholestatic liver years, new drugs that block hepatitis B virus (HBV) disease and disorders of bilirubin metabolism. replication have been developed and tested, such that there are now six licensed options. A major and distinctive function of the liver is to The effectiveness of each of these has been make and excrete bile. Bile facilitates digestion and characterized, and guidelines for their use have absorption of lipids and is also the major means been updated. Antiviral therapy of hepatitis B has of elimination of cholesterol and the breakdown been shown to prevent disease progression. products of metabolism, such as bilirubin. Persons with severe liver disease usually have altered Understanding the life cycle of hepatitis C virus bile formation and retention of the products (HCV). A landmark breakthrough in HCV research of bile and bilirubin, which results in . has been the recent growth of this virus in cell Disruptions in the steps of bilirubin elimination culture, which will permit more detailed studies of and bile formation are responsible for many of the the entire viral life cycle, including initial infection, severe inherited forms of liver disease in children. replication, packaging, and release of virus. Detailed

174 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Goals for Research

knowledge of these steps will permit identification of animal systems to study infectivity. The recent potential new approaches to treating the infection. description of a cell culture propagation method for a strain of hepatitis C may help overcome Demonstration of the efficacy and safety of these difficulties. Current therapies are effective a virus (HEV) vaccine. A landmark in only half of patients and are poorly effective or study conducted in Nepal has shown protective too toxic for patients with advanced liver disease, immunity against HEV infection with a three-dose patients with a solid organ transplant, or those schedule of a recombinant HEV vaccine. who have other serious co-morbidities, such as renal, cardiac, or cerebrovascular disease. The research goal in the area of viral hepatitis is to develop practical, safe, and effective means of Objectives: prevention, treatment, and control of all forms ß Develop a vaccine or specific means of of the disease. Viral hepatitis can be caused by prevention of hepatitis C. (Chapter 5: C3a) any one of five viruses that infect the liver in ß Develop safer and more effective means of humans, appropriately named hepatitis A, B, C, treating chronic hepatitis C that can be applied D, and E virus. Hepatitis A and E are forms of to all categories of patients. (Chapter 5: B2a, infectious hepatitis that are very contagious, occur B1b, C2a, C2b) in outbreaks of typically acute clinical courses, and ß Understand the factors underlying the are associated with poor sanitation and fecal-oral differential disease burden and poorer response spread. Both viruses can cause severe hepatitis, to therapy in African American patients with but they do not cause chronic liver injury or hepatitis C. cirrhosis. Hepatitis B, C, and D are forms of serum ß Better understand the structure and replication hepatitis that are less infectious, can cause chronic cycle of the hepatitis C virus to help develop infection, are blood-borne, and are spread largely new therapeutic targets and better small by parenteral or sexual routes. All five viruses have molecular therapies for this disease. (Chapter 5: been identified in the last 30 years, and tests to A3, B1a, B3a) identify infections and means of prevention with ß Better understand the host and HCV immune globulin or vaccines are available for four interactions that determine viral clearance of them (A, B, D, and E). The incidence of new versus persistence. (Chapter 5: A2, B1a, B3a) cases of viral hepatitis has been decreasing steadily in the U.S. for the last 20 years. Nevertheless, cases still occur and cases of chronic hepatitis Research Goal 11.6: Improve strategies for B and C remain common causes of cirrhosis use of current therapies of hepatitis B and develop and end-stage liver disease. Full control and new, improved treatment regimens. elimination of viral hepatitis will require several more breakthroughs in hepatitis research. Advances in hepatitis B research in the last 40 years have been impressive, but further efforts are needed for the complete control of this disease, Research Goal 11.5: Develop safe and including defining how to best use available effective means to prevent and treat hepatitis C. therapies in practice. There are currently at least six licensed therapies for hepatitis B, all of which Progress in developing a hepatitis C vaccine has lead to improvements in the disease when given been impeded by the lack of apparent immunity for 1-2 years; however, the optimal therapy or from re-infection and lack of cell culture and small combinations of therapies, how they are to be

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given, and for how long have yet to be identified. patients with concurrent treatment for HIV infection In addition, new classes of therapies that target is different from patients with mono-infection, other viral replication steps or elicit favorable and there is considerably less evidence for optimal immune responses would enhance treatment treatment regimens. Recently, tenofovir has been options for hepatitis B. shown to have more potent antiviral activity against HBV than adefovir in HIV/HBV co-infected persons. Objectives: The combination of tenofovir and emtricitabine ß Develop a better understanding of the is now recommended as standard of therapy for pathogenesis of hepatitis B in all its forms HBV/HIV co-infection. (acute, chronic, active, inactive). (Chapter 5: B1a, B2b, B3b) ß Better define the optimal means for treatment Research Goal 11.8: Define the causes of liver of chronic hepatitis B. (Chapter 5: B2a, B2b, disease associated with HIV and develop means to C1a, C1b, C3b) prevent and treat liver disease in HIV-infected persons. ß Understand the factors responsible for the ethnic and racial disparities in hepatitis B Patients with HIV infection are susceptible to a infection, which disproportionately affects Asian wide range of liver diseases, and the interactions of Americans in the U.S. these diseases with HIV infection and its therapies ß Conduct clinical trials to compare multimodality are complex and challenging. As patients with HIV therapies for hepatitis B. (Chapter 5: C1b) infection are surviving longer as a result of effective anti-retroviral therapy, liver disease has become an increasingly important cause of morbidity and Research Goal 11.7: Develop improved means mortality. Liver disease among persons with HIV to prevent and manage acute viral hepatitis. infection represents a major challenge to research. The spectrum of liver conditions among HIV-infected At present, only emergency liver transplantation persons includes acute and chronic viral hepatitis; has been shown to be effective in management alcoholic and non-alcoholic steatohepatitis; drug- of acute liver failure due to viral hepatitis. New induced liver injury; autoimmune conditions of the medical therapies are needed, as these diseases liver; bacterial, fungal, and protozoal infections can be severe, protracted, and even fatal. of the liver and biliary system; and liver and bile duct cancers, including lymphomas of the liver. Objective: Viral hepatitis is particularly problematic among ß Develop and evaluate new approaches to HIV-infected persons, many of whom are in risk therapy in all five forms of acuteviral hepatitis. groups with a high rate of hepatitis B and C. The (Chapter 5: B2a, C1a) optimal approach to therapy of hepatitis C among HIV-infected persons remains unclear, and better therapies are needed. HIV Infection and the Liver (Action Plan Chapter 6) Objectives: ß Define the prevalence and incidence ofliver Recent Research Advance disease in HIV-infected persons and identify the causes of liver disease associated with HIV, as Regimens to treat HIV/HBV co-infection. The well as their means of diagnosis, prognosis, and response to therapies for chronic viral hepatitis in management. (Chapter 6: B1a, B2a, B2b, B3, C3b)

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ß Identify the optimal approach to therapy of Objectives: HCV in HIV-co-infected individuals and apply ß Identify the underlying pathogenesis of non- new agents active against HCV as soon as alcoholic fatty liver disease. (Chapter 7: A3, B2a) possible to this important cohort of patients. ß Elucidate the basic mechanisms of pathogenesis (Chapter 6: A1b, A2, C1b) of . (Chapter 7: B1a, B2a) ß Develop noninvasive means to distinguish steatosis and steatohepatitis. (Chapter 7: B2b; Fatty Liver Disease (Action Plan Chapter 16, C1b) Chapter 7) ß Identify and test safe and effective means of treatment of both forms of fatty liver disease. Recent Research Advance (Chapter 7: B1b, B3a, B3b, C1a, C1b)

Treatment of non-alcoholic steatohepatitis (NASH). In a proof-of-concept study, the administration Drug-Induced Liver Disease of pioglitazone led to metabolic and histologic (Action Plan Chapter 8) improvement in subjects with NASH, justifying the need for larger clinical trials, which are ongoing. Recent Research Advance

Development of a diagnostic assay for Research Goal 11.9: Understand the basic acetaminophen toxicity. An assay for mechanisms of injury and develop means to acetaminophen adducts has been developed prevent and treat non-alcoholic and alcoholic fatty and shown to identify 90-100 percent of cases liver disease. of acetaminophen-induced acute liver failure in adults and children. These adducts are not present Fatty liver disease occurs in two major forms: in cases of acute liver failure of other known alcoholic and non-alcoholic, both of which causes, but are present in 12-19 percent of cases are marked by accumulation of fat in the liver of unknown cause. Thus, some idiopathic cases of followed by inflammation, liver cell injury, fibrosis, acute liver failure may be caused by unrecognized and cirrhosis. Alcoholic liver disease is a major or unacknowledged acetaminophen overdose—a cause of illness and accounts for up to half of finding that has major therapeutic implications. deaths from liver disease. Non-alcoholic fatty The test requires further modification to become liver disease is a somewhat newly described clinically useful, and its sensitivity for milder forms problem, but appears to be the major reason for of acetaminophen injury requires elucidation. liver test abnormalities among Americans and is an increasingly common cause of significant liver disease and the need for liver transplantation. Research Goal 11.10: Establish means to The cause of non-alcoholic fatty liver disease predict, prevent, diagnose, and treat hepatotoxicity is unknown, but it is closely linked to obesity, due to drugs, herbal medications, and diabetes, and high triglyceride levels and, thus, environmental toxicants. appears to be a part of the metabolic syndrome. There are no current means of treatment of either Drug-induced liver disease has become an form of fatty liver disease, other than abstinence increasingly important health problem in the U.S. for alcoholic forms and attempts at weight loss for Liver injury from medications is rare, but can the metabolic forms of fatty liver disease. be protracted, severe, and even fatal. Indeed,

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drug-induced liver disease is now the leading primary biliary cirrhosis (PBC) have been described, cause of death from acute liver failure. While including the Nod.c3c4 congenic mouse, the TGF-β medications rarely cause liver injury, the increasing receptor II dominant-negative mouse, and an IL-2 use of greater numbers of medications by the receptor α knock-out (-/-) mouse. Each of these American public has raised the importance of this mouse models develops liver disease and anti- problem. In addition, the American public has also mitochondrial antibody reactivity with specificity for been increasingly using herbal medications and PDC-E2, typical of the human autoantibody. Further combinations of minerals, vitamins, and natural work in the Mdr2 knock-out (-/-) mouse model for products, many of which can cause liver injury. primary sclerosing cholangitis (PSC) indicates that At the same time, there are few insights into why side-chain modification of ursodiol yields a bile acid medications damage the liver and why hundreds or with greater therapeutic activity against PSC than thousands of people can take a medication safely, standard ursodiol. These and additional models while a rare individual gets serious liver disease. under development will provide new opportunities Finally, drug-induced liver disease is challenging to for research into disease mechanisms that cannot be the physician, has many diverse manifestations, and accomplished in human research. diagnosis is often delayed or missed. For all these reasons, new approaches are needed to broaden the understanding of drug-induced liver injury and Research Goal 11.11: Determine the etiology, how to prevent or manage it properly. pathogenesis, and potential new targets for therapy of the three major forms of autoimmune Objectives: liver disease: (AIH), primary ß Develop reliable animal models or laboratory biliary cirrhosis (PBC), and primary sclerosing systems to study different forms of drug-induced cholangitis (PSC). liver injury. (Chapter 8: A3a, B3b) ß Elucidate the genetic basis of drug- and toxicant- The three major forms of autoimmune liver induced liver injury. (Chapter 8: C1) disease—AIH, PBC, and PSC—are distinctly ß Develop standardized methods to accurately different forms of liver diseases that are diagnose drug-induced liver toxicity. characterized by inflammatory destruction of (Chapter 8: A1) hepatocytes or the biliary system and clinical ß Develop predictive tests for risk of drug-induced features of autoimmunity. While uncommon, liver injury that may allow for prevention of serious all are important causes of chronic liver disease liver disease. (Chapter 8: C2b, C3) that may progress to cirrhosis, liver failure, need ß Develop effective means of treating drug-induced for transplantation, or liver or biliary cancer. liver injury. (Chapter 8: C2a) Current approaches to medical management are not curative and are sometimes completely ineffective. AIH has many common features Autoimmune Liver Diseases of prototypic autoimmune diseases, including (Action Plan Chapter 9) female predominance, typical autoantibodies, and responsiveness to corticosteroids and Recent Research Advance immunosuppressive therapies. PBC also has female predominance, typical autoantibodies, and seems to Animal models of autoimmune liver diseases. Rapid be unresponsive to standard anti-inflammatory or research progress in autoimmune liver diseases has immunosuppressive regimens, but does respond to been significantly hindered by the absence of animal treatment with ursodiol. In contrast, PSC has models. In the last year, three promising models for

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male predominance, is commonly associated remaining children have mutations in the gene with inflammatory bowel diseases IBD),( and is encoding NOTCH2, the receptor for Jagged1. refractory to all forms of conventional therapy, including treatment of associated IBD. Syndromes Genetic basis of diseases causing intrahepatic of AIH and PSC may occur in early childhood, but cholestasis in children. Studies of a number of have features that distinguish them from their adult cholestatic diseases of children have led to the counterparts with the same names. Many hurdles identification of genetic defects in bile synthesis, have impeded research progress in these diseases, formation, and secretion and in development of including among others their slow, indolent the biliary tree. These discoveries have also led clinical course, low prevalence, absence of animal to the development of new murine models that models, and the great difficulty of conducting provide new research opportunities. immunopathogenesis studies in human liver.

Objectives: Research Goal 11.12: Determine the ß Develop robust animal models to study molecular and genetic pathways responsible mechanisms of liver injury associated with for the major forms of inherited and early- autoimmunity and conduct preclinical studies of onset, severe liver diseases of childhood, novel treatments. (Chapter 9: B3b) including biliary atresia, , ß Define the geneticrisk alleles for each of the progressive familial intrahepatic cholestasis, three major forms of autoimmune liver disease, , alpha-1-antitrypsin deficiency, followed by identification of physiologic pathways neonatal hemochromatosis, and mitochondrial associated with these alleles that may contribute hepatopathies in order to devise potential new to understanding the pathogenesis or reveal new targets for therapy. opportunities for therapy. (Chapter 9: B3a) ß Identify novel biomarkers and define surrogate A number of liver diseases of early childhood, listed endpoints to assist in diagnosis, assess disease above, are often severe and lead to progressive liver activity, or predict natural history or response to failure and need for transplantation. While all of different treatments. (Chapter 9: C2) these diseases are rare, the most common—biliary ß Conduct natural history studies in childhood onset atresia—is also probably the least understood. autoimmune liver diseases to refine phenotype A surgical procedure, the Kasai procedure, may definitions, identify geneticrisk alleles, and search ameliorate the disease when performed early for potential environmental triggers. in life, but the majority of patients continue to (Chapter 9: A2) have progressive liver failure, ultimately requiring transplantation. While the genetic basis is known for some of the other forms of familial diseases, Pediatric Liver Diseases current knowledge of the genes and their molecular (Action Plan Chapter 10) pathways has yet to be translated into therapies for these diseases, and liver transplantation remains the Recent Research Advances only form of therapy for many patients.

Molecular basis of Alagille syndrome. Using a Objectives: variety of molecular approaches, Jagged1 (JAG1) ß Define the etiology and pathogenesis ofbiliary mutations can be identified in 94 percent of children atresia and identify new pathways for devel- with Alagille syndrome, and a proportion of the opment of potential therapies. (Chapter 10: C3a)

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ß Optimize current approaches to medical and Genetic Liver Diseases surgical therapy of biliary atresia. (Action Plan Chapter 11) (Chapter 10: C1a) ß For familial childhood liver diseases, determine Recent Research Advance their genetic basis, including primary alleles and modifying alleles, which will permit Unraveling the pathogenesis of hemochromatosis development of standardized genetic tests and and iron metabolism. In the past decade, identification of potential pathways for devel- numerous research discoveries have elucidated the opment of translational therapies. pathogenesis of hereditary hemochromatosis and (Chapter 10: A1b, B2a, C2) the pathways of iron metabolism that are altered in this disease. In 1996, mutations in the HFE gene were shown to account for the majority of cases Research Goal 11.13: Evaluate and improve of hemochromatosis, which was recapitulated existing adult medical and surgical therapies for in murine models having deletions of this gene. treatment of children with liver diseases. Subsequently, additional proteins regulating iron metabolism were identified, and their roles in the In addition to familial and congenital diseases disease were elucidated, including divalent metal of children that often have a severe course and transporter 1, transferrin receptor-2, hephaestin, present early in life, children may also be affected hemojuvelin, -1, and most recently by diseases that are found in adults, including hepcidin—a protein produced by hepatocytes that viral hepatitis, NASH, drug-induced liver disease, is the key regulator of iron absorption in the gut. fulminant hepatitis, autoimmune liver diseases, Commercial testing for hemochromatosis is now and other genetic diseases, such as Wilson disease. available, and further advances in this field are While medical therapies may exist for some of likely to fully elucidate the molecular mechanisms these conditions, such as viral hepatitis, typically responsible for this disease and its various they have not been carefully validated and manifestations. optimized for treatment of children. Furthermore, while liver transplantation is often successful and may be life-saving for end-stage liver diseases in Research Goal 11.14: Elucidate the molecular children, long-term outcomes, including effects of pathways responsible for hereditary forms of liver transplantation regimens on growth, development, disease, including hereditary hemochromatosis, and cognitive function, are unknown. Wilson disease, the porphyrias, cystic fibrosis, , and congenital hepatic Objectives: fibrosis; use knowledge of these pathways to devise ß Conduct clinical studies to validate use of novel approaches to treatment. medical regimens and liver transplantation for treatment of liver diseases in children. Hereditary hemochromatosis is the most common (Chapter 10: B1b) inherited liver disease in Caucasians, affecting ß Identify biomarkers and surrogate markers approximately 1 in 200 individuals. In this disease, for assessment of children with chronic liver excess iron absorption leads to serious damage diseases. (Chapter 10: A1a, B3) to multiple organs, including the liver, heart, pancreas, and other organs, and liver cancer. Early diagnosis and treatment with phlebotomy prevents all of the complications of this disease. Wilson disease is an uncommon cause of liver disease

180 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Goals for Research

due to abnormalities of copper transport and, like living donor liver transplants (LDLT) have been hemochromatosis, early recognition and treatment performed in the U.S., yet the potential benefit of the disease can prevent complications. There to liver transplant candidates of undergoing LDLT are five main forms ofporphyria that can affect compared to waiting for deceased donor liver the liver, and these rare diseases can cause severe, transplant (DDLT) until recently was unknown. disabling disease. Some, but not all, forms have A recent large cohort study demonstrated that treatments of varying efficacy. With longer survival LDLT was associated with lower mortality than of cystic fibrosis patients,liver disease is emerging the alternative of waiting for DDLT, although this as an important long-term complication that can reduction in mortality of the recipient must be lead to liver failure. Severe polycystic liver disease balanced against risks to the living donors. is an autosomal dominant condition that can lead to liver failure and is caused by genes distinct from those causing polycystic kidney disease. Collectively, Research Goal 11.15: Refine current for many of these diseases there has been rapid procedures in liver transplantation, including progress in identifying the molecular mechanisms assessment of potential transplant recipients, responsible; however, progress has been variable immunosuppressive regimens, and management in development of clinical genetic testing and of donors and recipients for living donor development of novel, effective therapies. transplantation, and improve management of recurrent liver diseases in transplanted patients. Objectives: ß For each of the genetic liver diseases, define the Liver transplantation is the standard of care for primary genes and modifying genes and patients with end-stage liver disease or acute their molecular pathways that lead to disease. liver failure. The most common procedure used is (Chapter 11: A1a, A3, B2a, B3, C2a) deceased donor orthotopic liver transplantation, ß Accelerate translational research to identify but living donor transplantation is available, new target pathways for treatment, including particularly for children and to a lesser extent development of animal models for preclinical for adult transplantation. The major reason for testing. (Chapter 11: C2b) transplantation is end-stage liver disease from any ß For diseases having no target for drug treatment cause; other indications include acute liver failure, or alternative approaches to treatment, develop liver cancer, and, rarely, metabolic diseases that approaches to gene therapy to correct the can be corrected with transplantation. Despite underlying defect. (Chapter 11: C3b) significant and continuing improvements in liver ß Develop clinically applicable noninvasive tests to transplantation with respect to organ procurement accurately measure metabolic consequences of and distribution, surgical techniques, and medical these diseases, such as iron or copper overload. management of the transplant patient since the (Chapter 11: C1, C3a; Chapter 16: C1b) 1960s, a number of challenges remain in this field. Among the problems are the continuing shortage of donor organs, premature death of transplant Liver Transplantation recipients due to complications of procedures or (Action Plan Chapter 12) immunosuppression, and recurrence of underlying liver disease after transplant, such as viral hepatitis Recent Research Advance or cancer. Ultimately, improvements in preventing the progression of the multiple different forms of Benefits and risks of living donor liver chronic liver diseases to end-stage liver disease transplantation. More than 2,000 adult-to-adult offers the best solution to the problems of

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transplantation, but for the foreseeable future liver The majority of patients who die of cirrhosis transplantation will continue to be an essential ultimately succumb to complications of portal form of therapy that requires further improvements hypertension, which include variceal hemorrhage, through research. ascites, spontaneous bacterial peritonitis (SBP), , and hepatorenal Objectives: and hepatopulmonary syndromes. Currently ß Further refine theModel for End-Stage Liver available techniques to diagnose and treat these Disease (MELD) and Pediatric End-Stage Liver complications have significant limitations and Disease (PELD) systems to optimize allocation of often do not significantly prolong life or eliminate for transplantation. (Chapter 12: A1) the need for liver transplantation. In addition, ß Identify biomarkers for adequate patients with advanced liver disease may suffer immunosuppression, active rejection, and from intractable fatigue and pruritus. . (Chapter 12: A2, C2b) ß Develop approaches to improve long-term Objectives: tolerance for allografts in order to minimize the ß Define in detail the pathophysiologic need for immunosuppressive drugs. (Chapter mechanisms that cause . 12: C2a, C1a) (Chapter 13: A3a) ß Improve treatment for recurrence of underlying ß Identify small molecular targets for interventions liver diseases, such as viral hepatitis, in to reduce portal hypertension. (Chapter 13: B3a) transplant recipients. (Chapter 12: B2b, C3a) ß Develop reliable, non- or minimally invasive methods to measure portal pressure and screen for . (Chapter 13: B3b, C3b) Complications of Liver Disease ß Better characterize the cause of increased (Action Plan Chapter 13) susceptibility to bacterial infections in cirrhosis, particularly SBP, and determine how to manage Recent Research Advance these infections. (Chapter 13: A3b, B1)

Pathophysiology of portal hypertension. Patients with cirrhosis have a hyperdynamic state in the Research Goal 11.17: Develop better means splanchnic bed that is caused, at least in part, of prevention, management, and treatment of by nitric oxide (NO). Vasodilation induced by acute liver failure. NO may be mediated by vascular endothelial growth factor (VEGF). In the liver, the vasodilator Acute liver failure is defined as the sudden onset response to NO is blunted, which in a rat of severe liver injury with signs of hepatic failure in model appears to be due to up-regulation of a person without previous liver disease. Acute liver endothelial phosphodiesterase-5, the enzyme failure accounts for up to 2,000 deaths each year responsible for degrading NO. Therefore, both in the U.S. and typically strikes previously healthy phosphodiesterase-5 and VEGF may be targets for individuals, including children and adolescents. therapy of portal hypertension. The major cause of acute liver failure in the U.S. today is drug-induced liver injury, either due to acetaminophen or to idiosyncratic injury due to Research Goal 11.16: Identify ways to a medication or herbal preparation. Other causes prevent or ameliorate the complications of portal include hepatitis A and B and autoimmune liver hypertension and cirrhosis. diseases. Strikingly, at least half of acute liver

182 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Goals for Research

failure in children and approximately one-quarter Animal models of . Advances of cases in adults are due to unknown causes in diagnosis and treatment of the form of human (idiopathic). While viruses are suspected to be the biliary cancer known as cholangiocarcinoma have cause of idiopathic acute liver failure, the actual been hampered by the absence of animal models cause has so far eluded research investigation. for detailed studies that are not possible in humans. Nevertheless, acute liver injury results in death or Three animal models for cholangiocarcinoma have need for liver transplantation in approximately now been described that should help advance the three-quarters of patients, and there are currently science and therapy of this disease. no therapies or means of temporary support for this dire complication of acute liver disease. Research Goal 11.18: Develop effective Objectives: strategies for early detection and treatment of ß Identify the cause(s) of idiopathic acute liver and cholangiocarcinoma failure. (Chapter 10: A3) in high-risk groups. ß Develop biomarkers that more accurately reflect hepatic regeneration and reserve in acute liver Malignant diseases of the liver and biliary tree failure. (Chapter 13: C2a) can be either primary or secondary to other forms ß Develop non-specific, hepatoprotective of cancer that metastasize to the liver. Primary therapies that improve survival or allow time liver cancers include the most common form, for liver transplantation in acute liver failure. HCC, and others, including cholangiocarcinoma, (Chapter 13: A1b, B2a) , fibrolamellar carcinoma, ß Develop and evaluate bioartificialliver support angiosarcoma, and other rare forms. Most cases devices that improve survival in acute liver of HCC arise in the setting of other chronic liver failure or allow for temporary support until a diseases and cirrhosis; thus, patients at risk include liver becomes available for transplantation. those with many common forms of chronic liver (Chapter 13: C3a) disease, such as viral hepatitis, alcoholic and non-alcoholic fatty liver disease, and essentially any other cause of chronic liver injury. HCC is a livEr and Biliary cancEr (action highly lethal disease, and current diagnostic and Plan cHaPtErS 14 and 15) medical treatments have limited efficacy. Liver transplantation is an option for cases having early Recent Research Advances diagnosis. Other forms of liver cancer, notably cholangiocarcinoma, have other distinctly different Genetic profiling of hepatocellular carcinoma risk factors and clinical behaviors and, most (HCC). An important research advance in HCC has notably, this form of cancer is a complication of been the description of the molecular signatures long-standing primary sclerosing cholangitis. of this form of cancer. Although in an early stage, these discoveries have diagnostic, prognostic, Objectives: and therapeutic implications, in that they may ß Identify new biomarkers for early detection eventually permit identification of new targets of primary liver cancers, particularly HCC and for therapy and stratification of patients based on cholangiocarcinoma. (Chapter 14: A2a; their type of cancer and individualized therapies. Chapter 15 C2b) More research is needed to fully realize the value of this advance.

Diseases of the Liver and Biliary System 183 Goaloalss for for Rese Rarcesearchh

ß Develop new imaging techniques that detect Genetic risk for gallstone disease. Researchers primary liver and biliary cancers in the setting of have identified variations in the gene encoding underlying chronic liver disease. (Chapter 14: hepatic cholesterol transporter ABCG5/G8 that A3; Chapter 15, A3; Chapter 16, C1b) are associated with gallstone disease in human ß Identify the cellular and molecular pathways patients. Finding ways to modulate this transporter leading to primary liver cancer in order to could lead to important new therapies to prevent identify potential new targets for therapy. or treat the formation of gallstones. (Chapter 14: A2b, C2, C3) ß Identify strategies to prevent HCC and cholangiocarcinoma in high-risk populations. Research Goal 11.19: Develop better means (Chapter 14: C1; Chapter 15: C1) to prevent and treat gallstones.

There are multiple diseases of the gallbladder Gallbladder and Biliary and biliary tree, including gallstones, acute Disease (Action Plan Chapter 15) , acalculous cholecystitis, primary sclerosing cholangitis, biliary atresia, choledochal Recent Research Advances , , and cholangiocarcinoma. However, gallstone disease is by far the most New approaches to prevent cholesterol gallstones. common of these conditions, affecting about 12 Human trials on prevention of gallstones have percent of the adult U.S. population. Gallstone not yet been initiated, but several studies in disease leads to approximately 700,000 animal models have suggested potential novel per year and is one of the most approaches. Fibroblast growth factor (FGF)-15, costly digestive diseases for the healthcare system. which is produced in the ileum in response to bile acid signaling through FXR, plays an important role Objectives: in gallbladder filling. Lack ofgallbladder filling may ß Determine the genetic basis for increased risk and predispose to gallstones, which perhaps explains protection from gallstone disease. (Chapter 15: the link between diseases of the terminal ileum A1, C2a) and gallstone formation. Furthermore, agonists of ß Better define the pathophysiologic basis of FGF-19 (the human homologue to mouse FGF- gallstone formation, including the role of bacterial 15) might play a role in prevention of gallstones. factors. (Chapter 15: B2) In another study in mice, targeted deletion of ß Identify biomarkers for gallstone formation. Gpbar1, a gene involved in regulation of cholesterol (Chapter 15: B3) secretion, led to resistance to gallstone formation in ß Design approaches to prevent gallstone response to a high-fat diet. Thus, inhibitors of this formation in high-risk groups. (Chapter 15: C3) cell-surface receptor for bile acids may be a means of decreasing the likelihood of gallstones.

184 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases MAJOR CHALLENGES AND STEPS Clinical research: Clinical research in liver TO ACHIEVE the RESEARCH GOALS diseases is hampered by limitations of standard criteria for case definition, need for and lack of Basic mechanisms of liver diseases: precision in disease assessment by , The mechanisms that trigger damage to absence of biomarkers and surrogate markers the liver are partially known. Development that are particularly needed for indolent of multidisciplinary and interdisciplinary diseases, and absence of a pipeline of potential collaborations between investigators interested new therapeutic interventions that might in liver diseases and basic scientists in areas emerge from basic and translational research. such as immunology, genetics, virology, oncology, When new approaches to treatment become molecular and cell biology, and other disciplines available, clinical trials will often require a would be greatly facilitated by creating the substantial number of research centers because necessary resources for collaborative studies, of low disease prevalence. In partnership such as gene, liver, and serum repositories of with the U.S. Food and Drug Administration, samples from well-defined patients. best practices for clinical trial design could be developed, along with the formation of public- Translational research: The absence private partnerships with the pharmaceutical of robust animal models for many liver industry to generate interest in drug diseases has greatly hampered progress in development for uncommon liver and biliary understanding these diseases or preclinical diseases. testing of novel therapies. Identification of new models may allow for more rapid progress, and further studies of animal models are needed. Findings from these models need to be rapidly applied to clinical research.

Diseases of the Liver and Biliary System 185 Endomicroscopy (upper) and histologic section (lower) of normal human colon crypts. New imaging technologies, such as confocal endomicroscopy, can enable more accurate diagnosis and monitoring of digestive diseases, such as colorectal cancer in high-risk patients.

Image courtesy of Dr. Ralf Kiesslich. Reprinted from Gastroenterology, 132, Kiesslich R, Goetz M, Lammersdorf K, Schneider C, Burg J, Stolte M, Vieth M, Nafe B, Galle PR, Neurath MF. Chromoscopy-guided endomicroscopy increases the diagnostic yield of intraepithelial neoplasia in ulcerative colitis, pp. 874-882, Copyright 2007, with permission from Elsevier.

 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Bioengineering, Biotechnology, and Imaging

SUMMARY OF RESEARCH GOALS

The luminal structure of the gastrointestinal (GI) tract and the inherent regenerative capacities of many cell types within the organs of the digestive system afford significant opportunities for the development of innovative technologies and approaches to the diagnosis and treatment of digestive diseases. The

Commission recommends several research goals that are intended to capitalize on emerging technologies and facilitate medical and surgical care of digestive disease patients. Ready access to much of the digestive tract is permitted by endoscopic or minimal access approaches for biopsy or resection of tissue.

Research is needed to evaluate the risks and benefits of such procedures compared to conventional surgical techniques. Advances in stem cell biology and regenerative medicine could be applied to foster the repair and regeneration of diseased tissue within the digestive system. Innovative scaffolds to guide the growth of complex digestive organ structures will need to be developed in order to realize the potential of promising tissue engineering approaches. The development of advanced imaging technologies and interactive simulators that allow surgeons to plan and practice procedures using patient-specific images would reduce therisk of trauma to healthy tissue during treatment. Collectively, these research goals will lead to innovative technologies that have the potential to significantly improve patient outcomes and enhance treatment efficacy for many digestive diseases.

Bioengineering, Biotechnology, and Imaging 187 INTRODUCTION AND BACKGROUND Enhanced application and utilization of CT, MRI, and PET imaging modalities have Detection, diagnosis, and treatment of improved the ability to make accurate digestive diseases present both challenges structural assessments of tumors and and opportunities for technology development inflammatory processes in these organs. given the diverse anatomy of the digestive Endoscopic access to the pancreatic and biliary organs. Procedural techniques and imaging systems is now routine, allowing more accurate strategies must be designed for both luminal diagnosis and therapeutic options for patients and solid organs. Advances in technology with benign ductal disorders or with malignant require scientific collaboration among conditions. Three-dimensional reconstructive multiple clinical and scientific disciplines, imaging has improved pre-operative procedural including gastroenterology, surgery, planning to predict residual hepatic volume , engineering, mathematics, physics, after resection and to more accurately stage computational science, and others. patients with malignant tumors. Multimodality imaging of the liver, including real-time Luminal structures: The most common ultrasonography, has facilitated the application disorders of the GI tract develop from the cells of ablation technologies for selective treatment that line the intestinal lumen—the mucosa. of tumors in some patients. Increasing This is the site of origin of GI cancers, benign knowledge of the molecular characteristics ulcers, and a variety of inflammatory disorders of tumors metastatic to liver disease, such as that occur in all age groups. While the gastrointestinal stromal tumors (GIST) and (esophagus, stomach, and duodenum) and neuroendocrine tumors, enables assessment colorectum are readily accessible to endoscopic of the efficacy of chemotherapeutic agents, evaluation, the small bowel remains a vast including imatinib or , in the organ that is largely inaccessible to repeat management of these patients. endoscopic evaluation and treatment of the luminal surface. The luminal surfaces Imaging: Advances in imaging technology of the colon, rectum, and foregut can be are revolutionizing the noninvasive detection visualized, allowing abnormalities to be of digestive diseases. Improvements in CT biopsied, ablated, or resected using endoscopic technology have enabled the delivery of high- approaches or provide needed data to plan resolution images for three-dimensional surgical procedures. New technologies for reconstructive imaging that mimics endoscopic imaging the intestinal lumen have yielded observations. Emerging technologies—fusion of improved diagnostic capability, although their ultrasound and CT imaging, for example—allow therapeutic applications remain limited. CT precise, real-time interventions and improved and MRI imaging techniques have improved to procedural planning. New contrast agents and evaluate structural disorders of the intestinal agents that reflect metabolic activity of tissues, wall and peritoneal cavity, allowing the use of such as PET imaging, have improved the ability minimal access surgical technologies in lieu of to detect otherwise occult lesions in solid organs conventional operative procedures. or in the peritoneal cavity.

Solid organ structures: The liver, biliary Emerging technologies: Advances in device system, and pancreas remain common sites development have led to remarkable new tools of malignant and inflammatory disorders. for manipulating the GI tract and peritoneal

188 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases structures. Based on the evolution of these platforms. The development of simulators manipulable devices from a remote operating capable of mimicking highly complex GI platform, new procedures such as natural orifice procedures to allow physicians and surgeons transluminal endoscopic surgery (NOTES) to gain needed practice and expertise before are being implemented in the clinic. Clinical proceeding to patient procedures will foster trials are in progress to introduce an operating improved patient safety and quality of care endoscope via the mouth for passage through in rapidly changing new technologies. Recent the stomach wall into the abdominal cavity to advances in computational science and haptic remove or repair an organ. Both trans-vaginal technology have allowed the initial delivery of and trans-gastric cholecystectomies (removal simulators with high-fidelity to create virtual of the gallbladder) have been reported. Linking environments for these educational purposes. robotic surgical devices, whereby a As the pace of technological innovation in manipulates fine instruments in a patient procedural technologies is rapid, simulators from a console with high-definition three- that keep pace with this change to maintain the dimensional imaging, is increasingly applied to skill sets of the gastroenterology and surgical surgical procedures of the abdomen, with the workforce will need to be developed. Advances result that surgeries can be performed with in technology will also enable the combination more precise and miniaturized instruments to of pre-procedural, patient-specificsimulation, reduce trauma to healthy tissue. so that a surgical team can plan and practice the procedure using images of patient-specific Tissue engineering/regenerative anatomy. It is conceivable that simulators medicine: The field of tissue engineering will also be used as part of privileging and regenerative medicine has just begun programs to assess procedural competency of to be explored in the GI luminal and solid gastroenterologists and surgeons. organs with the goal of reconstructing functionally and structurally normal tissues. The identification of the intestinal stem cell RECENT RESEARCH ADVANCES niche provides a vital first component to this work, as this cell type will be a progenitor for Image-enhanced endoscopy growth of a new mucosal structure to replace a damaged small intestine. Similarly, the Advances in optical imaging have greatly development of appropriate scaffolds on which expanded the sensitivity and specificity of to grow new liver cells, pancreas cells, and endoscopic observations. High magnification intestinal tissue will be necessary to create , , replacement organs for those patients with autofluorescenceimaging, narrow band hepatic, pancreatic, or intestinal failure. The imaging, and optical coherence tomography structural diversity and complexity of the have enhanced the ability to detect areas of digestive tract pose a significant challenge for mucosal abnormalities, including pre-malignant the development of regenerative therapies for changes of dysplasia and early cancers. These digestive diseases. technologies have allowed enhanced detection of areas of flat and depressed colorectal neoplasia, Simulation training: Preparing the GI enhanced identification of Barrett’s epithelium endoscopy and surgical workforce for the with dysplasia, and identification of dysplastic future requires sophisticated educational mucosa in the stomach.

Bioengineering, Biotechnology, and Imaging 189 Technological advances have allowed endoscopic Development of the endoscopic ultrasound procedures to replace more invasive surgical (EUS) probe procedures in several complex areas of GI disease. Improved design, materials, and delivery tools The development of an ultrasound probe capable for endoluminal stents have provided improved of being passed into the GI tract with the palliation for malignant strictures, refractory endoscope has made possible the examination fistulas, and complex post-operative surgical of the mucosa, bowel wall, and adjacent organs disorders with lesser morbidity than conventional with enhanced specificity. The ultrasound surgical approaches. probe has revolutionized the evaluation of periampullary lesions, allowing more accurate The development of operating endoscopes with identification and definition of pancreatic multiple ports to allow improved endoscopic and distal biliary masses, more precise tissue techniques, including suturing, injection, and sampling with fine needle aspiration biopsy, and manipulable instruments, has facilitated improved staging of malignancy for pre-operative endoscopic treatment of luminal conditions evaluation. Submucosal and mural lesions of that once required surgical approaches. the GI tract from the esophagus through the first portion of the duodenum—regions that Effective technologies for mucosal ablation were previously occult to conventional imaging and endoscopy—are readily evaluated by For those areas of the GI tract amenable EUS. Intrarectal ultrasound has standardized to endoscopic reach, a variety of ablation staging of rectal cancers, allowing appropriate tools have been developed to treat benign application of neoadjuvant strategies for patients and malignant conditions. For patients with with rectal cancer and identifying those patients pre-malignant disorders of the foregut and amenable to local resection. colorectum (including Barrett’s esophagus and others) and those with more advanced Evaluation of the small bowel lumen neoplasms who are otherwise not candidates for major surgical procedures, a variety of ablation The introduction of the video capsule endoscope technologies, such as photodynamic therapy, has revolutionized imaging of the small bowel radiofrequency ablation, and sclerosing agents, mucosa. This once hidden luminal structure now offer new treatment options. For patients is now readily evaluated for many common with GI bleeding disorders or lesions, enhanced disorders, including Crohn’s disease, idiopathic devices and agents to treat these lesions via inflammatory diseases of the small bowel, and the endoscope have been developed, sparing malignancy. Occult bleeding from the small patients considerable morbidity associated with bowel may be identified, addressing a long- major surgical procedures. standing, unresolved clinical dilemma prior to this technology. New technologies to detect colorectal neoplasia have been developed. While screening Combined modality imaging and colonoscopy of the prepared colon remains the molecular imaging gold standard, significant advances in detection of pre-malignant and adenocarcinoma of the Recent studies have established that FDG-PET colon have been developed, such as the use allows identification of peritoneal and lymph of CT colonography (virtual colonography, node metastases for colorectal and other GI colonoscopy), video capsule endoscopy, cancers. The use of specific, targeted molecular quantitative immunochemical agents to silence metabolic activity of tumors testing, and fecal DNA analysis. has been particularly valuable in conjunction

190 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases with FDG-PET as the tracking modality. opportunities for TE/RM efforts. The most Patients with imatinib-sensitive GIST tumors significant progress of TE/RM research in the GI or octreotide-sensitive neuroendocrine tumors tract has been in the creation of functional liver exhibit molecular silencing on FDG-PET tissue. Significant advances have been made scanning, which provides a valuable marker of in the ability to isolate functional hepatocytes efficacy of these agents. and maintain their phenotype and functionality in vitro; the ability to isolate biologic scaffolds Tissue engineering/regenerative medicine that support functional hepatocytes; and in (TE/RM) in the GI tract understanding the appropriate growth factors and cytokines needed to maintain hepatic The regenerating intestinal epithelium with growth in vitro. its inherent stem cell population offers unique

GOALS FOR RESEARCH 18

Research Goal 12.1: Define the optimal Research Goal 12.2: Develop innovative procedural approach for patients with digestive technology for the diagnosis and treatment of disorders amenable to endoscopic, image-guided, luminal disease. or minimal access surgery. In addition to surveillance and detection of Innovations in minimally invasive surgery offer disease, endoscopic techniques are used to several potential advantages over traditional biopsy or resect diseased tissue. Endoscopic surgical techniques or endoscopic procedures. improvements would further reduce the risks Rigorous evaluation of these new procedures is of the procedure and augment the therapeutic needed to determine their cost-effectiveness and applications of the technology. efficacy in improving patient outcomes. Objectives: Objectives: ß Develop and validate a method to perform ß Evaluate efficacy and outcome measures, “molecular” biopsy of luminal abnormalities in including quality-of-life, for innovative surgical real time. technologies. ß Develop improved instrumentation for ß Perform a cost analysis of new surgical methods . compared to traditional procedures. ß Develop improved virtual endoscopy technology ß Conduct rigorous studies of physiologic and to access the luminal space of the GI tract. immunologic response to minimal access surgery to determine whether biologic advantage exists for these procedures. Research Goal 12.3: Use tissue engineering and regenerative medicine approaches to develop innovative treatments for digestive diseases.

18 Research Goals are numbered for ease of reference only; the numbers do not indicate prioritization of scientific topics.

Bioengineering, Biotechnology, and Imaging 191 Goaloalss for for Rese Rarcesearchh

Advances in stem cell biology provide an Objectives: opportunity to transform the treatment of ß Develop new PET tracers for clinical use, digestive diseases. The stem cell population that including markers of proliferation, tumor- supports ongoing regeneration of the intestinal specific antigens, and markers of apoptosis and epithelium can be harnessed to regenerate inflammation. tissues of the GI tract. To reach this goal, ß Develop intraoperative high-energy gamma better understanding of the stem cell niche and beta detectors to enhance intraoperative and development of biologically compatible localization. scaffolds that can direct the growth of the ß Develop energy delivery and real-time tracking complex structure of the GI tract are needed. devices to optimize local image-guided The esophagus, in particular, would benefit from interventions. regenerative approaches, as there are limited ß Develop improved devices for facilitating single surgical options for repair of this organ. The small port laparoscopic procedures, intraluminal intestine represents another prime target for stem procedures, and natural orifice surgeries. cell-based approaches to the treatment of short bowel syndrome, inflammatory bowel diseases, and other conditions. Research Goal 12.5: Develop high-fidelity interactive simulators of the digestive system. Objectives: ß Identify and isolate local stem cell populations in Advances in computer simulation provide an the GI tract for tissue engineering applications. opportunity to transform technical and cognitive ß Develop scaffolds, both naturally occurring and training in GI endoscopy and surgery. Virtual synthetic, to support growth and differentiation environments can be used for training, prior to of cell populations indigenous to the GI tract. initiation of patient procedures. Simulators could ß Develop tissue engineering and regenerative facilitate the acquisition of new procedural skills medicine methods to treat diseases of the by physicians who have completed training and digestive organs. also could be used for certification and testing to ensure procedural quality.

Research Goal 12.4: Expand the application Objectives: and integration of imaging and procedural ß Define the optimal use of simulation in training technologies to deliver targeted interventions with the procedural workforce, including metrics, minimal tissue injury to patients with digestive transference, competency assessment, and disorders. acquisition of new technologies. ß Define the value of simulation in developing Image-guided therapeutics can accurately and new procedures to facilitate procedural design specifically deliver treatments to diseased tissue and the prediction of outcomes. and minimize damage to surrounding healthy ß Develop high-fidelity simulators to allow tissue. Novel agents to visualize markers of disease multimodality procedural rehearsal. must be tested and validated in human patients. New devices that facilitate noninvasive imaging and manipulation of tissues could minimize trauma to the patient and improve therapeutic efficacy.

192 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases MAJOR CHALLENGES AND STEPS Regenerative medicine: The GI tract TO ACHIEVE the RESEARCH GOALS lags behind other tissues in terms of tissue engineering/regenerative medicine research. Translational and clinical research: Fostering research on this topic and A critical challenge for the field is finding translation of results into clinical trials would ways to attract and support translational accelerate progress in the field. clinicians—physicians who interact with patients and can bridge the basic science Fostering research teams: A multicenter questions and technologies. Training of consortium for the evaluation and treatment new investigators in the area of technology of luminal disease could be established. feasibility and assessment could also be Such collaboration among expert users of encouraged. In addition, enhanced support for advanced or novel technologies would enhance randomized clinical trials, including studies of the design and execution of randomized, advanced endoscopic and other technologies, controlled trials in human patients. Further, would accelerate the validation of new, state- the development of multidisciplinary centers of-the-art procedures. Increased inclusion of for technology design, development, and endoscopists and surgeons on study sections testing would promote scientific investigation is critical for ensuring appropriate review of among relevant areas of expertise that proposals for testing new technologies. include GI medicine and surgery, engineering, imaging, chemistry, computer science, and Academia-industry collaboration: others. Inclusion of scientific expertise that Small technology companies working to is traditionally considered to be outside of develop imaging or intraprocedural guidance the biomedical sciences would promote rapid technology often do not have sufficient progress in the field. Finally, creation of a capitalization, and value is based primarily patient registry would encourage collaboration on a small amount of academically based and sharing of resources. These challenges intellectual property. Finding ways to foster could be addressed by a workshop to convene collaboration between academia and small investigators for an early assessment of industry would encourage development and promising new technologies and to identify key testing of new devices and technologies arising questions and studies for implementation in from translational research. Management of the near future. conflict-of-interest and intellectual property issues are key matters to address.

Bioengineering, Biotechnology, and Imaging 193  Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Conclusion: Common Themes and Steps for Implementation

PRESSING NEED FOR A SUBSTANTIAL the digestive system that confront healthcare RESEARCH EFFORT IN DIGESTIVE providers on a daily basis, including GI bleeding, DISEASES abdominal pain, jaundice, and diarrhea. Despite these advances, many of the current Disorders of the digestive system affect the solutions for these problems remain imperfect majority of the U.S. population at some time and costly. In addition, progress on other diseases throughout life. These disorders include a has occurred at a much slower rate, including large spectrum of diseases, ranging from acute, the highly prevalent functional GI disorders, foodborne infections to chronic, debilitating many forms of cancer of the digestive system, diseases, such as inflammatory bowel diseases, and pancreatitis. Acute enteric infections remain and life-threatening conditions, such as cancer an important cause of morbidity and mortality, and liver failure. Some conditions, such as particularly in children in underdeveloped heartburn and constipation, are so prevalent countries. Other conditions associated with the that many may not view them as disease rising prevalence of obesity, such as non-alcoholic entities, while a large number of conditions are steatohepatitis, are likely to increase the burden serious, relatively rare, and often below the of digestive diseases in the U.S. The Director radar screen of public attention. of the NIH, recognizing both the great burden of digestive diseases in the U.S. and the great Many decades of NIH-funded research in diversity and complexity of basic, translational, digestive diseases have led to a detailed and clinical research approaches that could be understanding of the digestive system, the brought to bear on the problem, chartered the causes of many diseases, and improved National Commission on Digestive Diseases to treatments that are now the standard of make recommendations to the NIH for future care. Among the many stories of success are research on digestive diseases, which are the discovery of H. pylori as a major cause of described in this long-range research plan. ulcer disease; development of highly effective acid-blocking drugs as treatments for ulcer COMMON THEMES and heartburn; discovery of the multiple forms of viral hepatitis and development Although the Commission’s research plan of curative treatments and preventive contains a large number of goals and specific programs; development of biologic therapies objectives, common themes transcend many of for inflammatory bowel diseases IBD);( these recommendations. These themes include: and implementation of effective screening (1) a focus on major scientific disciplines that programs to prevent colorectal cancer. Dramatic are the engine for creating new knowledge; technological innovations in noninvasive (2) approaches to the organization of research imaging and testing, endoscopic procedures, and efforts, such as multidisciplinary basic or minimally invasive surgery now permit rapid clinical research teams and networks, that are and accurate diagnosis and treatment of many required for effective translation of laboratory of the most common, serious problems involving findings for the benefit of patients with digestive

Conclusion: Common Themes and Steps for Implementation  diseases; (3) the development of important health and are perturbed in disease processes. research resources that provide infrastructure Extensive additional work is needed to obtain a necessary for modern scientific discovery; and comprehensive understanding of the many cell (4) efforts that must be undertaken to ensure types in the digestive system, including their the availability of a highly specialized workforce normal development and senescence, cell-cell to conduct digestive diseases research of the communication, and function as part of whole future. It is the position of this Commission that organs, systems, or organisms. Increasingly, strong support by NIH for coordinated research understanding complex conditions, such as the planning efforts to address these common functional GI disorders, will require integration themes is critical for the continued success of of knowledge about the digestive system with digestive diseases research and, as will become other systems, particularly the central nervous apparent, may be more broadly applicable to system, and increased understanding of the many other areas of health and disease-oriented biologic basis of symptoms and behaviors. research. Maintaining current momentum and These approaches will be the foundation for the facilitating new research approaches for these discovery of potential targets for intervention common themes by all parties in the research in disease processes with drugs or biologics. process will encompass the major strategies Increasingly, studies of cell and molecular needed for implementing the research plan. biology will use not only currently available These strategies are not described in any specific techniques, but also more complex, integrative order, since all are thought to be of high priority. systems biology approaches to understand the biology and pathobiology of the digestive system. Theme 1: Increase the Fundamental Knowledge Base for Understanding Strategy 1.2: Define the genetic basis of Health and Digestive Diseases. digestive diseases.

Basic and translational biomedical research Medical research has entered an era where is the foundation and core of NIH-supported comprehensive analysis of whole genomes digestive diseases research. The diverse of organisms will facilitate the discovery of research programs supported by NIH have the genetic basis of not only classic genetic provided a robust and steady stream of new diseases, but also of the role of common genetic knowledge about the normal, healthy digestive variation in complex non-Mendelian diseases. system and how it is perturbed in diseases. For example, recent ground-breaking discoveries Research discoveries have provided critical concerning the genetics of IBD will likely propel data necessary to develop better ways for and transform research in numerous areas preventing, diagnosing, treating, or curing of translational and clinical research in IBD; digestive diseases. Steps that are needed parallel approaches offer great potential for to ensure that this process continues are advances in many other digestive diseases. The encompassed in the strategies listed below. complete unraveling of risk alleles, gene-gene interactions, and gene-environment interactions Strategy 1.1: Elucidate the molecular in the pathogenesis of diseases will undoubtedly basis of biologic and pathologic processes be challenging, but the expected benefits of in the digestive system. this line of investigation are considerable. These benefits include a better understanding Many advances in digestive diseases research of critical pathways in pathogenesis, clues to have emerged from detailed studies of the potential environmental factors, and potential molecules, cells, and pathways that underlie clinical research advances, including diagnostic

196 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases tests, new therapeutic agents, and improved toward more beneficial microbial species understanding of genetic variability in responses through the use of agents such as prebiotics to medicines (pharmacogenomics). In addition, or probiotics, is an equally high priority. The studies of genetics and modifications that potential for modifying the microbiome of influence gene activity (epigenetics) are central to the digestive system to maintain health is an understanding cancers of the digestive system. important new research opportunity that will be pursued through efforts such as the NIH Human Strategy 1.3: Understand the role of Microbiome Project. microbes in digestive health and disease. Strategy 1.4: Harness research in The normal human GI tract exists in symbiosis immunology, inflammation, and with the complex mixture of microbes inside transplantation to improve our it, which plays an important role in the understanding of the digestive system and function of the digestive system. In addition, its diseases. infectious agents cause substantial morbidity and mortality throughout the world as the The digestive system is an important component major cause of diarrheal diseases and chronic of the overall immune system of the body. infectious diseases, such as viral hepatitis. Its unique functions and structures—known Microbes in the gut also probably contribute collectively as the mucosal immune to the pathogenesis of a variety of complex system—play a critical role in both host defense disorders, including IBD. Chronic infections, and tolerance. Many, if not most, diseases of such as H. pylori gastritis or chronic viral the digestive system are characterized by hepatitis, are important causes of cancer. immune and inflammatory components, which Further microbiological research is needed to play a central role in disease pathogenesis. identify and fully understand the pathogenesis Some diseases, such as celiac disease, are of infections of the digestive system, to develop characterized by loss of tolerance to ubiquitous effective strategies, such as vaccines, for their dietary antigens. Immunity to alloantigens is prevention, and to understand the role of the a major barrier in transplantation of liver and entire internal microbiological ecosystem small bowel. Immunological research has led to in maintaining health and contributing to important advances, such as the development disease. New technologies must be developed of protective vaccines and specific therapies, to understand the collection of microbes and including interferon for viral hepatitis and their genomes (microbiome) and to identify infliximab forIBD. Further research is needed and understand both pathologic and health- to define the specific roles of the immune system maintaining processes caused by microbes. in a wide range of complex diseases, such as Prevention of diseases caused by infectious IBD, celiac disease, necrotizing enterocolitis, agents through vaccination has been one of the pancreatitis, viral hepatitis, autoimmune greatest contributions of medical science in liver diseases, and pre-malignant conditions. modern times, but many potentially preventable Progress in immunological research holds infectious diseases lack vaccines. Identifying promise for identifying new targets for therapies highly effective anti-microbial treatments for and potential approaches to disease prevention, both acute and chronic infectious diseases of as well as amelioration of the barriers to the digestive system, or ways to tip the balance transplantation.

Conclusion: Common Themes and Steps for Implementation 197 Strategy 1.5: Discover the cellular have found clinical applications. It is expected and molecular basis of development, that new technologies will continue to appear. regeneration, and aging of the Newer technologies, such as expression arrays, digestive system. high-throughput DNA sequencing, proteomics, and metabolomics, generate large amounts of Some components of the digestive system have data that have required parallel development an astonishing capacity for regeneration and of computational methods to analyze the self-repair. The one-cell-thick lining of much of data. High-resolution imaging techniques the GI tract exhibits rapid turnover of cells, with have revolutionized both research and clinical continuous replacement due to progenitor cells practice. While support for hypothesis- that differentiate into multiple cell types. While driven, laboratory-based investigation is hepatocytes have a long lifespan, the liver also the cornerstone of NIH-supported research, has remarkable regenerative capacity under continued progress in digestive disease conditions of cell death or resection. While much research requires the development and research in disease pathogenesis has focused availability of new technologies to enable both on mechanisms of cell death, less attention basic and clinical research. has been given to the role of regenerative mechanisms in disease processes until recently. Theme 2: Translate Fundamental New Rapid progress in stem cell and developmental Knowledge for the Direct Benefit of biology research has energized this area of Individuals. biologic research in the digestive system. Relatively little attention has been devoted to changes in the digestive system that occur in To achieve the long-term goals of this plan, aging. Research in stem cell and progenitor cell increased attention should be devoted to biology, developmental biology, and aging offers translational research, that is, moving the potential for profound insights into many knowledge gained from basic research into different diseases, including cancer, as well patient-based clinical research in digestive as the potential means for new cell and tissue diseases and then encouraging adoption of engineering-based approaches to treatment. successful practices in the broader healthcare community. In contrast to the prototypic Strategy 1.6: Support the development and laboratory-based research project, clinical application of new research technologies research projects typically require longer time for digestive diseases research. periods to plan and execute, have substantial resource and personnel requirements and higher costs, and often encounter additional Many advances in digestive diseases research regulatory and ethical hurdles not found in have directly resulted from the development of animal or in vitro research. Human subjects new technologies that permit investigators to research, particularly clinical trials, may approach previously insurmountable problems. require interaction with different government The list of technologies is long and includes agencies, such as the U.S. Food and Drug recombinant DNA techniques, isolation and Administration (FDA), require development of propagation of clonal cell populations, creation partnerships with industry, and may be subject of genetically modified animals, production of to the limitations of the existing healthcare monoclonal antibodies, high-throughput DNA system. Meeting these overall requirements for sequencing, siRNA inactivation, and high- clinical and translational research will require a throughput screening of molecular libraries. combination of strategies. Not surprisingly, many of these techniques

198 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Strategy 2.1: Refine the phenotypes of implications extending beyond a physiologic or patients with digestive diseases. pathologic parameter and providing additional insights into the disease process. Biomarkers Progress in understanding diseases often correlate with or are predictive of diagnosis, requires an iterative process of discovery, stage, rate of progression, response to treatment, observation, and a more refined description of or any other clinically meaningful characteristic. the disease, followed by additional research. A A surrogate marker has the additional feature simple example of this process is the discovery of being a predictor that can be used to assess and understanding of the different forms of viral the disease process itself and can be used as an hepatitis. Initially recognized only as “infectious” endpoint in a clinical trial, faithfully predicting hepatitis, research ultimately led to a detailed eventual clinical outcomes. Ideal biomarkers understanding of the multiple different forms and surrogate markers should be observations of hepatitis and discovery of effective treatment that can be made noninvasively and repeatedly, and prevention approaches suitable for each with modest cost and high reproducibility. With form. Assembling the research phenotype of these goals, much work on identifying biomarkers subjects with a particular digestive disease has concentrated on easily obtainable fluids, requires an organized approach with common such as serum, plasma, urine, or blood, but definitions for all clinical and laboratory biomarkers may include any type of observation, parameters, standardized methods to obtain such as images or biophysical measurements, laboratory data, and construction of databases like measures of liver stiffness. Many digestive that include novel research parameters, such as diseases currently have no or only a few imperfect genetic alleles or response to a new treatment. biomarkers. The availability of robust biomarkers Increasingly, analysis of disease phenotypes and, particularly, surrogate markers would will include not only routine clinical and greatly improve the efficiency of clinical trials and laboratory observations, but also whole genome potentially lead to improvements in clinical care. information, proteomic profiles of biofluids, serological and microbiological information, Strategy 2.3: Define thenatural history data from advanced imaging studies, and and risk factors for digestive diseases psychosocial information. Full understanding of through epidemiologic research. disease processes may also require longitudinal observation of the evolution of disease over time, For many digestive diseases in the U.S., simple as in observational natural history studies or population-based descriptive information in treatment trials. Research in many complex is lacking or incomplete. Patient registries digestive diseases will likely benefit from a and long-term natural history studies will concerted, organized effort to define more permit opportunities to discover many highly refined disease phenotypes that will important features of disease processes, underpin the discovery of the fundamental such as environmental factors, interacting basis of digestive diseases, including symptoms co-morbidities, response to treatment, quality- and clinical manifestations, as well as new of-life information, and health economics data, approaches for prevention and treatment. as well as provide information needed

Strategy 2.2: Discover biomarkers and for design of clinical trials. New epidemiologic surrogate markers for digestive diseases. research is needed for many digestive diseases in order to generate new testable hypotheses, to Biomarkers and surrogate markers are properly design clinical trials, and to inform all components of a patient phenotype with stakeholders in medical policy decisions.

Conclusion: Common Themes and Steps for Implementation 199 Strategy 2.4: Develop new, innovative NIH should play an important role in the design technologies for clinical applications. and conduct of critical clinical trials, particularly when it is unlikely that the private sector alone Research on advanced new technologies has will conduct these research trials. The newly revolutionized diagnosis and treatment of developed Clinical and Translational Science numerous digestive diseases. Among these Award program of the NIH National Center for are endoscopy-based imaging and treatment Research Resources (NCRR) will play a vital role techniques, minimally invasive surgery, in academic clinical research programs. To meet including robotically assisted surgery and the goal of improving health for all, research tissue ablation, and high-resolution CT, MRI, in digestive diseases supported by NIH must and PET imaging technologies. Continued provide information about special populations, improvements in all of these technologies such as women, children, minorities, and other will undoubtedly provide new opportunities disproportionately affected populations that can for clinical research and improved diagnosis be used to address health disparities. and treatment. Newer technologies, such as nanotechnology, cell-based treatments, tissue Strategy 2.6: Bridge the gap between engineering, and organ assist or replacement controlled clinical trials and dissemination devices also offer promise for the future. of new knowledge into clinical practice. Development of these technologies is often primarily supported by industry, and academia- The discovery that an intervention has industry partnerships should be encouraged. efficacy in a carefully controlled, randomized Additional partnership opportunities exist clinical trial is not the final step in translation between the NIH and FDA to ensure that of a discovery from the laboratory bench adequate research information is available to the bedside of a patient with a digestive for informed decision-making regarding the condition. Further research is often required clinical application of new technologies. to demonstrate effectiveness in broad patient populations, to identify and overcome hurdles Strategy 2.5: Develop new means to prevent, that prevent widespread adoption of new cure, or treat digestive diseases through treatments, to determine how to use therapies clinical trials. in combination or sequentially with other forms of treatment, and to deal with additional For decades, adequately powered, randomized post-marketing assessments of the risks clinical trials have been the cornerstone for and benefits of therapies. These issues may evaluating the potential benefit of new drugs, become the subject of professional practice biologics, devices, behavioral treatments, or guidelines, but all too often the evidence base combinations of these approaches to managing is inadequate to provide sound guidance to digestive diseases. As noted above, the design practitioners for important questions that and conduct of important clinical trials is arise in the clinical setting. Close collaboration complex and often requires the participation between practitioners, industry, NIH, and of well-trained research teams, availability of other government agencies will be required to subjects willing to participate in the research, identify the highest priority areas that require research infrastructure, the opportunity to additional clinical research investments to solve create new resources such as repositories and these problems. NIH can facilitate this process databases, industry partnerships, adherence to through education and awareness campaigns numerous regulatory guidelines, and adequate and by sponsoring conferences, including funding, both in dollar amount and duration. consensus development conferences.

200 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Strategy 2.7: Support clinical insurmountable hurdle for research progress. research teams. The lack of sufficient research specimens may be due to different reasons, such as rarity of As for basic and translational research, clinical a disease, difficulty of obtaining inaccessible research on digestive diseases increasingly specimens from humans, limited financial requires the formation of teams of individuals or organizational resources to collect and with diverse expertise, including outstanding maintain samples, or an array of technical clinical knowledge and leadership skills; issues, such as how to define, obtain, and store expertise in evaluation and treatment of patients; different types of specimens. The resources clinical trial design; statistical evaluation; needed for research include, among others, training and monitoring of research support, cells, cell lines, tissues, sera, antibodies, such as study nurses and coordinators; creation DNA, and, in the case of human specimens, of databases; expertise in the various regulatory associated clinical annotations. Increasingly, and compliance steps needed for clinical research; innovative research involves computational and knowledge about procedures to effectively analysis of complex data sets that have been collaborate with other research partners, produced by other investigators, exemplified by such as industry. Clinical research projects whole-genome single nucleotide polymorphism provide important opportunities to leverage (SNP) data that describe individual genetic the investment in ongoing clinical research by changes in large numbers of subjects. The supporting additional ancillary clinical or basic NIH and other research organizations must research projects that use patient, specimen, strive to find efficient, cost-effective ways to or data resources of the parent study. Clinical make the necessary specimens and data sets research projects are also important for ensuring widely available to investigators. While the a continuing pipeline of clinical investigators by cost of building and maintaining repositories providing opportunities for research fellowship is substantial, the cost of these resources is and career development programs. often much lower than the cost of supporting the development of multiple resources and Theme 3: Develop Research Resources technologies used by individual investigators. and Infrastructure. Strategy 3.2: Create and make available As indicated in the preceding themes, new new animal models for digestive technologies and translational research have diseases research. revolutionized biomedical research. More than ever, the rapid application of research discoveries For over a century, progress in biomedical depends on the availability of not only expensive, research has depended on experiments complex technologies, but also the appropriate conducted with animals to answer questions “raw materials” for research, which include with approaches that are not feasible in various types of specimens and data and highly humans or in vitro systems. For the foreseeable trained, specialized research teams. future, NIH must continue to encourage and support research using animals. A Strategy 3.1: Increase the availability substantial fraction of current research in of specimens, data, and computational digestive diseases is conducted in animals. methods for research in digestive diseases. Animals provide access to well-characterized, standardized samples and the potential for detailed physiologic and pathologic The lack of availability of well-characterized observations not possible in humans, as well as specimens for research is frequently an

Conclusion: Common Themes and Steps for Implementation 0 preclinical models to test the safety and efficacy mathematics, engineering, and behavioral of new therapeutic agents. Genetically modified and social sciences. Collaboration among animals provide the opportunity to study the basic, translational, and clinical investigators role of specific genes and pathways. Animals will be required for rapid application of new raised in germ-free conditions enable studies fundamental discoveries to benefit individuals of the effect of microbes on normal biology with digestive diseases. and disease processes. Important techniques, such as high-resolution whole-body imaging, Theme 4: Maintain a Pipeline of Research are now available for research in animals. Investigators for the Future. Further development is needed of noninvasive, in vivo diagnostic tools for the assessment of The long-term success of the Nation’s investment GI phenotypes in animal research, such as in digestive diseases research requires that steps small animal MRI, ultrasound, PET, SQUID, be taken to ensure a steady stream of entrants and breath tests, among others. Research into the biomedical workforce, representing the in model organisms, including worms, flies, best and brightest new investigators willing and fish, will increasingly permit rapid to make long-term commitments to careers identification of critical pathways, targets, and in research. The research training, individual potential therapies. To this end, development fellowship, and career development programs and utilization of improved data mining tools of NIH and, more recently, the Loan Repayment will facilitate screening and comparison of Programs for Clinical and Pediatric Research large-scale genomics data from various animal have been important components of maintaining models of disease. Developing, procuring, and the pipeline. At the conclusion of research maintaining animals for research are currently training and career development programs, very expensive processes, and centralized young investigators are at a particularly investment and infrastructure are needed to vulnerable period where career choices may be ensure that such resources are available to the strongly influenced by grant funding paylines, wider community of scientists. success rates, and the job satisfaction of their mentors. Mentorship is a critical component Strategy 3.3: Support team research. of the research training process that does not receive adequate support or recognition. Trainees Many biomedical research projects require need to have opportunities to be immersed in the close collaboration of multiple, highly trained activities of strong research teams where there individuals with different types of expertise. is adequate infrastructural and educational Increasingly, biomedical research on digestive support. The Nation needs a diverse biomedical diseases is characterized by team science. The workforce to address the numerous digestive creation of an effective research team requires diseases research problems of a complex society, not only a vision for the research that needs and efforts should be taken to ensure adequate to be done, but also leadership, organizational development of women and minorities in skills, stable institutional and financial support, the workforce. rewards that incentivize and reward all members of the team, as well as more mundane Strategy 4.1: Support research training, requirements for space, time, technologies, and individual fellowship, and career specimens or data. Innovative research teams of development programs. the future will include members with expertise in areas not traditionally found in many These programs should encourage innovative biomedical research teams, including physics, research programs designed to attract

202 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases outstanding young investigators, support Strategy 4.4: Enhance career development mentors, and provide high-quality educational educational workshops and conferences. experiences. Success rates for funding of career awards in digestive diseases should be high Many NIH Institutes and Centers, as well as enough not to discourage young investigators professional organizations and foundations, from choosing a research career path. Stipend sponsor career development conferences and and salary support should be increased to keep workshops that provide necessary training pace with competitive salary requirements for in the many procedures and processes—the the different stages of training career positions. “nuts and bolts”—of career development. Career grants should provide competitive These programs are widely viewed as salary support commensurate with the serving an essential need, and they should academic rank of the individual. be expanded to the extent that every young investigator on a digestive diseases research Strategy 4.2: Support mentorship. track is able to participate in these workshops. Additional workshop opportunities are needed In recognition of the critical requirement for for mentoring. Research conferences and mentorship, NIH should explore a variety workshops sponsored by NIH should encourage of potential mechanisms to incentivize and attendance of young investigators by providing reward mentorship activities. Mentorship is funds specifically for this purpose. essential for progress in digestive diseases research by the next generation of scientists, Strategy 4.5: Reduce the financial burden yet potential mentors and their institutions are for new investigators. not often given reasons to value mentoring over other activities with more visible benefits, such The NIH Loan Repayment Programs for Clinical as grant awards and research publications. and Pediatric Research may encourage career choices in research by providing additional Strategy 4.3: Maintain a substantially support for loan repayment. The success rate higher success rate for R01-equivalent for applicants in digestive diseases-related grants for new investigators in digestive research fields should equal that ofNIH overall. diseases than that of established Consideration should be given to expanding investigators. the loan repayment programs to include investigators in additional research fields New investigators must have a reasonable besides clinical or pediatric research. chance of success at obtaining an R01-equivalent award, as it is currently the de facto standard Strategy 4.6: Assure a diverse workforce. required by academic institutions for remaining in an academic research career. This may be Programs should be encouraged to target achieved by establishing higher paylines for new individuals in under-represented minorities PIs or using funds set aside expressly for this to enter careers in biomedical research with a purpose. NIH should provide bridging support for focus on digestive diseases. Potential steps to be new investigators who have no means of research taken include educational programs targeted to support pending review of revised applications. high school and college students and dedicated stipends for individuals at later stages of research training.

Conclusion: Common Themes and Steps for Implementation 0 Strategy 4.7: Provide short-term training The large number of goals, objectives, and in digestive diseases research. challenges identified in this research plan that must be addressed to comprehensively solve Adoption of complex new technologies in the problems of maintaining digestive health research frequently requires in-depth training, and conquering the many forms of digestive but for a limited period of time. Training disease represents a formidable challenge to programs targeted at short-term training all parties in the research process: the research in new technologies for digestive diseases community of investigators, study participants, research should be encouraged. professional research and patient advocacy organizations, industry, foundations, and public Strategy 4.8: Encourage entry of PhD funding organizations, such as the NIH. It is scientists into translational and clinical hoped that each of these research partners will research in digestive diseases. use this research plan as a scientific guidepost to identify ways to promote promising future Both nationally and internationally, there research opportunities to address the burden is a large pool of young PhD scientists with of digestive disease. The NIH will continue to training in basic scientific disciplines that solicit broad stakeholder input as it oversees could potentially be tapped to contribute implementation of this long-range research plan to the pipeline of translational and clinical for digestive diseases through the activities investigators in digestive diseases research. of such coordinating bodies as the Digestive Young investigators could be encouraged Diseases Interagency Coordinating Committee. to concentrate on the digestive system by development of short-term educational In particular, a large number of individual steps programs that expose individuals to research will need to be taken by these research partners opportunities, experiences of successful PhD over the 10-year time horizon of the research investigators, and funding opportunities at NIH plan to achieve its goals and objectives. The in digestive diseases research. members of the Commission recognize that research progress often occurs in a “bottom up” fashion, not only rapidly outstripping the best laid efforts of scientific planners, but also as Steps For Implementation Of The a result of the innovative ideas and initiative Research Goals of individual scientists and research teams. However, it is also clear that certain types This long-range plan for digestive diseases of research projects and program, as well as research from the National Commission on specific resources and infrastructure, require Digestive Diseases results from deliberations central, “top-down” organization led by funding of the appointed and ex officio members of institutions with the flexibility to apply optimal the Commission with the assistance of many mechanisms to address promising research individuals who contributed additional directions as they arise. Because of these valuable ideas and insights. The plan describes considerations and others, the Commission’s numerous broad goals and specific objectives recommendations are targeted primarily at to improve the health of the Nation through the research goals that should be achieved, but basic, translational, and clinical research that not on the administrative, policy, or procedural will lead to the discovery of improved ways approaches that NIH might use to achieve those to prevent, treat, or cure a diverse group of goals. The Commission recommends that the conditions that affect the GI tract, liver, biliary NIH maintain an approach focused on the goals system, and exocrine pancreas.

204 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases set forth in this research plan that includes a special needs and opportunities; and programs substantial and balanced portfolio of programs that ensure a pipeline of new investigators to with three major elements: strong support of meet the continuing needs of digestive diseases investigator-initiated research project grants; research in the future. initiatives designed to strategically address

Conclusion: Common Themes and Steps for Implementation 0 0 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases APPENDIX 1: Summary List of Recommended Research Goals and Common Themes

The National Commission on Digestive Diseases recommends a series of research goals to guide the NIH and other entities in addressing scientific opportunities for digestive diseases research over the next 10 years. In addition, the Commission identified several common themes that, if addressed, would promote progress broadly across many areas of digestive diseases research. The Research Goals and Common

Themes are numbered for ease of reference and are not listed in priority order.

RESEARCH GOALS 1.6: Define the physiologic basis for intestinal growth and adaptation and alterations with aging. Research on the Basic Biology of the 1.7: Define the physiologic basis of energy Digestive System balance, appetite, and satiety and their roles in obesity. 1.1: Develop new technologies to isolate, 1.8: Define the physiology of neuroimmune characterize, cultivate, and manipulate stem pathways involved in inflammation. cells of the digestive system for research and 1.9: Develop a comprehensive profile of intestinal therapeutic applications. genes that regulate mammalian absorptive 1.2: Understand how particular cell and tissue functions. niches are generated and maintained in the 1.10: Identify critical pathways in murine and other embryonic pancreas, liver, biliary tree, and in vivo models to develop targets for treatment digestive tract. of obesity and other disorders of nutrient 1.3: Exploit the advanced understanding of absorption and metabolism. 1.11: Define pathways that regulate barrier Wnt-APC-β-catenin signaling in human epithelial function to develop new, effective function and transport function. treatment strategies for colorectal cancer. 1.12: Define molecular pathways leading to differ- 1.4: Delineate specific signaling pathways, entiated absorptive and secretory functions. transcriptional regulation, and other interac- 1.13: Develop means to measure and manipulate tions that mediate critical patterning events epithelial function. in gut endoderm, which generate and 1.14: Define the basic cellular and molecular maintain its distinctive major derivatives (GI mechanisms responsible for neural activation, tract, liver, and pancreas). integration, and regulation in the ENS. 1.5: Translate advances from laboratory research 1.15: Understand the structure, function, and in gut development to identify disease regulatory mechanisms responsible for mechanisms and therapeutic targets for motility in the GI tract. diverse GI disorders (e.g., congenital 1.16: Develop research tools to investigate the disorders, cancer). structure and functional organization of the ENS.

APPENDIX 1: Summary List of Recommended Research Goals and Common Themes 0 1.17: Characterize the neuromuscular phenotypes 2.4: Understand the immune functions of the of human GI tissues. muscularis, integration between mucosal 1.18: Integrate cellular events in ENS with whole and muscle immune responses, and how system physiology and translate findings to inflammatory processes contribute to the pathophysiologic conditions. pathogenesis and maintenance of functional 1.19: Translate knowledge of the ENS in digestive GI and motility disorders. health and disease into diagnostics and 2.5: Understand peripheral and central pain and therapies for human disease. sensory pathways and how these pathways are 1.20: Determine the biologic activities of the affected in functional GI and motility disorders. microflora in healthy humans. 2.6: Understand the noxious visceral signaling 1.21: Determine the mechanisms of host-microbial causing nausea and vomiting related to interactions that are necessary to maintain gastric neuro-electrical and/or motor health and contribute to pathological dysfunction and the bi-directional processes in disease. brain-gut interactions. 1.22: Determine the role of epithelial cells in 2.7: Understand the role of the microflora in mucosal host defense and inflammation. functional GI disorders and motility disorders. 1.23: Understand the role of antigen-presenting 2.8: Use information from studies of animal cells in the mucosal immune system. models and cellular physiology to 1.24: Understand trafficking of mucosal cells to understand the integrated function of the various parts of the mucosal immune system. musculature and the intrinsic and extrinsic 1.25: Understand mucosal unresponsiveness (oral nervous systems. tolerance) and mucosal regulatory T cell 2.9: Characterize the factors in diabetes that lead development. to the development of functional GI and 1.26: Understand the differentiation and function motility diseases. of mucosal lymphocytes and other immuno- 2.10: Determine how genotype contributes to or logically active cells. predisposes patients to the development of 1.27: Develop mucosal vaccination strategies. functional GI and motility disorders. 2.11: Determine the role of food in the development Functional Gastrointestinal Disorders and of functional GI and motility disorders. Motility Disorders 2.12: Develop new technologies and therapeutic approaches to effectively treat patients with 2.1: Understand the molecular and cellular events functional GI and motility disorders. that yield normal motility, sensory behavior, 2.13: Evaluate therapeutic outcomes and the and integration between motility and secretory impact of doctor/patient interactions to activity in the GI tract and the pathophysiology determine effective treatments for functional of functional GI disorders and motility disorders. GI and motility disorders. 2.2: Understand the development of the GI tract and brain-gut interactions and determine how Infections of the Gastrointestinal Tract the aging process and differences in sex and gender affect gut development and function 3.1: Elucidate the etiology, epidemiology, and and brain-gut interactions. pathogenesis and improve diagnostic tests 2.3: Understand the components and functional for intestinal infections. interactions of the peripheral (autonomic 3.2: Improve the prevention and treatment of and enteric) and central nervous systems in intestinal infections. normal physiology and in functional GI and 3.3: Understand and modulate the long-term intestinal motility disorders. and non-intestinal consequences of GI infection.

208 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases 3.4: Understand the human microflora and Inflammatory Bowel Diseases microbiome in health and disease and modulate them for beneficial effects. 5.1: Establish an objective basis for determining clinical diagnosis, detailed phenotype, and Cancers of the Digestive System disease activity in IBD. 5.2: Develop an individualized approach to IBD 4.1: Develop population-based strategies for risk evaluation and management based on screening and prevention of digestive genetic susceptibility. cancers. 5.3: Modulate the intestinal microflora to prevent 4.2: Ascertain the importance, detection, and or control IBD. natural history of pre-malignant conditions 5.4: Effectively modulate the mucosal immune progressing to digestive cancer. system to prevent or ameliorate IBD. 4.3: Evaluate health disparities in digestive cancer 5.5: Sustain the health of the mucosal surface. etiology, risk, treatment management, 5.6: Promote regeneration and repair of injury in IBD. and outcomes. 5.7: Provide effective tools for clinical evaluation 4.4: Improve outcomes in the care of digestive and intervention in IBD. tract cancer patients. 5.8: Ameliorate or prevent adverse effects of IBD 4.5: Develop biomarkers to detect neoplasia, on growth and development in children target therapy, and evaluate therapeutic and adolescents. response in digestive cancers. 4.6: Evaluate nutriceutical, probiotic, chemo- Intestinal Failure and Regeneration, Nutri- preventive, and targeted therapies in tional Disorders and Support, Surgically digestive cancers. Modified Gut, and Transplantation 4.7: Understand the molecular and cellular mechanisms common to all digestive cancers. 6.1: Define mechanisms of intestinal growth 4.8: Determine the risk factors and pathogenesis and differentiation. of squamous carcinoma and adenocar- 6.2: Develop new strategies to treat short bowel cinoma of the esophagus and devise new syndrome and intestinal failure. methods for detection, diagnosis, treatment, 6.3: Improve the success of intestinal and prevention of these diseases. transplantation. 4.9: Understand the molecular profiles of various 6.4: Understand and treat the metabolic and nutri- types of gastric cancer to improve risk tional consequences of bariatric procedures stratification, prevention, and treatment. and other surgical modifications of the gut. 4.10: Define the genetic and environmental factors 6.5: Optimize nutritional support of patients with contributing to pancreatic cancer and its GI disorders. precursor lesions and devise new methods for early detection, treatment, and prevention. Diseases of the Oropharynx and Esophagus 4.11: Identify genetic and environmental risk factors for colon cancer and devise improved 7.1: Understand the neurobiology of oropha- approaches for screening, early diagnosis, ryngeal structure and function in health treatment, and prevention of colon cancer. and disease. 4.12: Understand the etiology, natural history, 7.2: Understand the clinico-pathologic mecha- prevention, and management of rare nisms leading to and/or associated with GI cancers. GERD and identify novel molecular, physiologic, and anatomic targets for more effective and rational treatment.

APPENDIX 1: Summary List of Recommended Research Goals and Common Themes 0 7.3: Define the mechanisms responsible for of the premature infant, including genetic esophageal injury and repair, with particular susceptibility, microflora, and immune/ emphasis on the interactions among compo- inflammatory processes. nents of the esophageal wall. 8.10: Develop novel predictive, therapeutic, and 7.4: Understand the epidemiology, natural preventive approaches for necrotizing enterocolitis. history, and outcomes of eosinophilic 8.11: Determine the genetic bases, mechanisms, esophagitis and identify targets for more natural history, and clinical phenotypes of rational and effective therapy. eosinophilic gastrointestinal disorders and 7.5: Understand the etiopathogenesis of Barrett’s identify/develop novel therapeutic compounds. esophagus, determine risk factors associated with its progression, and identify novel Diseases of the Colon and Rectum targets and/or therapies for chemopre- vention and treatment. 9.1: Establish mechanisms of colonic injury and 7.6: Understand the etiology and biology of repair to use as a basis for development of esophageal neuromuscular function in health therapeutic interventions. and disease and develop more effective 9.2: Understand colonic mucosal absorption in treatments. health and disease. 9.3: Determine the role of gut microflora in Diseases of the Stomach and Small Intestine health and disease states of the colon. 9.4: Establish the cause of diverticular disease 8.1: Understand mechanisms and improve and its complications, with modulation of treatment of H. pylori diseases. disease. 8.2: Reduce and prevent NSAID peptic diseases. 9.5: Understand mechanisms and develop tools 8.3: Define the genetic, bacterial, and host factors for early diagnosis of colon ischemia and that regulate epithelial and inflammatory cell angioectasia. responses to injury in gastric mucosa. 9.6: Improve management of anorectal disorders. 8.4: Understand the basis of rare gastric cancers, 9.7: Improve the understanding and develop effective measures for earlier and management of fecal incontinence. more accurate diagnosis, and develop effective 9.8: Reduce the frequency and severity of treatment strategies. radiation injury to the colon. 8.5: Determine the genetic, molecular, and 9.9: Determine causes of appendicitis and integrated physiologic bases of intestinal water, modulate the course of the disease. nutrient, and electrolyte transport. 8.6: Improve treatment, prevention, and diagnosis Diseases of the Pancreas of malabsorptive and diarrheal diseases. 8.7: Understand pathogenic mechanisms of celiac 10.1: Determine the biologic factors involved in disease, autoimmune diseases, and allergic the pathogenesis of acute pancreatitis, with diseases of the digestive system. particular emphasis on the mechanisms of 8.8: Improve screening, diagnosis, prevention, and tissue necrosis and systemic complications. treatment of celiac disease and of autoimmune 10.2: Understand the transition from acute to and allergic disorders of the bowel. chronic pancreatic injury, particularly with Characterize and define the mechanisms respect to the role of alcohol. underlying the association of celiac disease 10.3: Understand genetic factors and their interac- with autoimmune and neurological diseases. tions with exogenous insults, with respect to 8.9: Understand the pathogenesis of necrotizing pathogenesis, complications, and natural history enterocolitis and the unique susceptibility of pancreatitis and other pancreatic disorders.

210 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases 10.4: Develop and validate therapeutic interven- treatment, and prevention of cholestatic liver tions for treatment and/or progression of disease and disorders of bilirubin metabolism. pancreatitis and its complications. .: Develop safe and effective means to 10.5: Understand the neurobiology of the prevent and treat hepatitis C. pancreas with respect to mechanisms of .: Improve strategies for use of current pain and neurogenic inflammation. therapies of hepatitis B and develop new, 10.6: Define theepidemiology and clinical improved treatment regimens. course of acute and chronic pancreatitis, .: Develop improved means to prevent and including alcoholic pancreatitis, autoimmune manage acute viral hepatitis. pancreatitis, and cystic fibrosis, through .: Define the causes of liver disease associated population-based studies in adults and with HIV and develop means to prevent and children. treat liver disease in HIV-infected persons. 10.7: Develop more accurate and useful .: Understand the basic mechanisms of injury approaches to the diagnosis of chronic and develop means to prevent and treat pancreatitis by functional, radiologic, non-alcoholic and alcoholic fatty liver disease. endoscopic, or pathologic/cytologic means. .0: Establish means to predict, prevent, 10.8: Define the role of pathologic lesions, such diagnose, and treat hepatotoxicity due to as pancreatic intraepithelial neoplasms, drugs, herbal medications, and environ- and other factors that may correlate with mental toxicants. the risk of malignant transformation in .: Determine the etiology, pathogenesis, chronic pancreatitis and cystic neoplasms and potential new targets for therapy of and map their morphologic and molecular the three major forms of autoimmune progression. liver disease: autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary Diseases of the Liver and Biliary System sclerosing cholangitis (PSC). .: Determine the molecular and genetic 11.1: Define the molecules, processes, and pathways responsible for the major forms pathways that underlie normal liver cell of inherited and early-onset, severe liver function, which can then be applied to diseases of childhood, including biliary understanding the cellular and molecular atresia, neonatal hepatitis, progressive basis of disease processes. familial intrahepatic cholestasis, Alagille 11.2: Understand the cellular mechanisms of liver syndrome, alpha-1-antitrypsin deficiency, injury, inflammation, repair, andfibrosis and neonatal hemochromatosis, and mitochon- develop effective means for monitoring and drial hepatopathies in order to devise treating diseases caused by these processes. potential new targets for therapy. 11.3: Define the molecular and cellular mecha- .: Evaluate and improve existing adult medical nisms underlying liver development and and surgical therapies for treatment of regeneration in health and disease and children with liver diseases. apply these findings to developing improved .: Elucidate the molecular pathways respon- therapies for liver disease. sible for hereditary forms of liver disease, 11.4: Delineate the normal pathways of uptake, including hereditary hemochromatosis, metabolism, and secretion of bile salts, Wilson disease, the porphyrias, cystic bilirubin, and other biliary lipids and solutes; fibrosis, polycystic liver disease, and characterize the alterations in these pathways congenital hepatic fibrosis; use knowledge that participate in the pathogenesis of liver of these pathways to devise novel diseases; and develop means for diagnosis, approaches to treatment.

APPENDIX 1: Summary List of Recommended Research Goals and Common Themes 211 11.15: Refine current procedures inliver COMMON THEMES transplantation, including assessment of potential transplant recipients, THEME 1: Increase the fundamental knowledge immunosuppressive regimens, and base for understanding health and management of donors and recipients for digestive diseases. living donor transplantation, and improve management of recurrent liver diseases in Strategies for Implementation: transplanted patients. 1.1: Elucidate the molecular basis of biologic 11.16: Identify ways to prevent or ameliorate the and pathologic processes in the complications of portal hypertension digestive system. and cirrhosis. 1.2: Define the genetic basis of digestive diseases. 11.17: Develop better means of prevention, 1.3: Understand the role of microbes in management, and treatment of acute digestive health and disease. liver failure. 1.4: Harness research in immunology, 11.18: Develop effective strategies for early inflammation, andtransplantation detection and treatment of hepatocellular to improve our understanding of the carcinoma and cholangiocarcinoma in digestive system and its diseases. high-risk groups. 1.5: Discover the cellular and molecular basis 11.19: Develop better means to prevent and treat of development, regeneration, and aging gallstones. of the digestive system. 1.6: Bioengineering, Biotechnology, Support the development and and Imaging application of new research technologies for digestive diseases research. 12.1: Define the optimal procedural approach for THEME 2: Translate fundamental new knowledge patients with digestive disorders amenable for the direct benefit of individuals. to endoscopic, image-guided, or minimal access surgery. Strategies for Implementation: 12.2: Develop innovative technology for the diagnosis and treatment of luminal disease. 2.1: Refine the phenotypes of patients with 12.3: Use tissue engineering and regenerative digestive diseases. medicine approaches to develop innovative 2.2: Discover biomarkers and surrogate treatments for digestive diseases. markers for digestive diseases. 12.4: Expand the application and integration of 2.3: Define thenatural history and risk imaging and procedural technologies to deliver factors for digestive diseases through targeted interventions with minimal tissue epidemiologic research. injury to patients with digestive disorders. 2.4: Develop new, innovative technologies 12.5: Develop high-fidelity interactive simulators for clinical applications. of the digestive system. 2.5: Develop new means to prevent, cure, or treat digestive diseases through clinical trials. 2.6: Bridge the gap between controlled clinical trials and dissemination of new knowledge into clinical practice. 2.7: Support clinical research teams.

212 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases THEME 3: Develop research resources 4.2: Support mentorship. and infrastructure. 4.3: Maintain a substantially higher success rate for R01-equivalent grants for new Strategies for Implementation: investigators in digestive diseases than that of established investigators. 3.1: Increase the availability of specimens, 4.4: Enhance career development educational data, and computational methods for workshops and conferences. research in digestive diseases. 4.5: Reduce the financial burden for new 3.2: Create and make available new animal investigators. models for digestive diseases research. 4.6: Assure a diverse workforce. 3.3: Support team research. 4.7: Provide short-term training in digestive diseases research. THEME 4: Maintain a pipeline of research 4.8: Encourage entry of PhD scientists into investigators for the future. translational and clinical research in digestive diseases. Strategies for Implementation:

4.1: Support research training, individual fellowship, and career development programs.

APPENDIX 1: Summary List of Recommended Research Goals and Common Themes 213 APPENDIX 2: Rosters of the National Commission on Digestive Diseases and Its Working Groups

Chairperson Executive Director

Stephen P. James, MD Robert D. Hammond, PhD Director Robert D. Hammond Associates, LLC Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health

Appointed Commission Members

Bruce R. Bacon, MD Mitchell B. Cohen, MD Director Director Division of Gastroenterology & Division of Gastroenterology, Hepatology & Nutrition St. Louis University School of Medicine Cincinnati Children’s Hospital Medical Center

Barbara L. Bass, MD, FACS Margaret M. Heitkemper, RN, PhD John F. & Carolyn Bookout Distinguished Chairperson Endowed Chair Department of Biobehavioral Nursing & Health Systems Department of Surgery University of Washington The Methodist Hospital Jane M. Holt Richard S. Blumberg, MD Co-President Professor of Medicine and Chief National Pancreas Foundation Gastroenterology Division David A. Lieberman, MD Brigham and Women’s Hospital Professor and Chief John M. Carethers, MD Division of Gastroenterology Professor of Medicine Department of Medicine Chief, Division of Gastroenterology Oregon Health and Science University University of California, San Diego Nancy J. Norton, BS Maurice A. Cerulli, MD Founder and President Chief International Foundation for Functional Division of Gastroenterology & Hepatology Gastrointestinal Disorders New York Methodist Hospital Pankaj J. Pasricha, MD Eugene B. Chang, MD Professor of Medicine Martin Boyer Professor of Medicine Chief Department of Medicine Division of Gastroenterology & Hepatology University of Chicago School of Medicine

214 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Appointed Commission Members (continued)

Daniel K. Podolsky, MD Robert S. Sandler MD, MPH President Professor of Medicine and Epidemiology Doris and Bryan Wildenthal Distinguished Chair Chief, Division of Gastroenterology and Hepatology in Medical Science University of North Carolina at Chapel Hill UT Southwestern Medical Center Joanne A. P. Wilson, MD Kenton M. Sanders, PhD Professor of Medicine Professor and Chairman Division of Gastroenterology Department of Physiology and Cell Biology Duke University Medical Center University of Nevada School of Medicine

Ex Officio Commission Members

Alexis Bakos, PhD, RN Jag H. Khalsa, PhD National Institute of Nursing Research National Institute on Drug Abuse

Lisa Begg, DrPH, RN Marguerite Klein, MS, RD Office of Research on Women’s Health National Center for Complementary and Alternative Medicine Beth Bell, MD, MPH Centers for Disease Control and Prevention Dennis Lang, PhD National Institute of Environmental Health Sciences Commander Brooks D. Cash, MD, FACP, MC, USN National Naval Medical Center Susan F. Marden, PhD, RN National Institute of Nursing Research Chhanda Dutta, PhD National Institute on Aging John Milner, PhD National Cancer Institute David P. Goldman, MD, MPH United States Department of Agriculture Griffin P. Rodgers, MD, MACP National Institute of Diabetes and Digestive and Raj K. Goyal, MD Kidney Diseases VA Boston Healthcare System Michael Rogers, PhD Gilman Grave, MD National Institute of General Medical Sciences Eunice Kennedy Shriver National Institute of Child Health and Human Development Annette Rothermel, PhD Brian Harvey, MD, PhD National Institute of Allergy and Infectious Diseases U.S. Food and Drug Administration Laura Seeff, MD Jay H. Hoofnagle, MD Centers for Disease Control and Prevention National Institute of Diabetes and Digestive and Francisco S. Sy, MD, DrPH Kidney Diseases National Center on Minority Health and Health Christine A. Kelley, PhD Disparities National Institute of Biomedical Imaging and Samir Zakhari, PhD Bioengineering National Institute on Alcohol Abuse and Alcoholism

APPENDIX 2: Rosters of the National Commission on Digestive Diseases and Its Working Groups 215 Rosters of Commission Working Groups

Each working group was led by a Chair and Vice Chair chosen from among the appointed members of the Commission and was composed of six to ten additional experts in each topic area who were selected after a public nomination process. Working group members were encouraged to consult informally with colleagues in the digestive diseases research community to ensure that this research plan reflects the broadest possible input. It is not possible to recognize by name all individuals who contributed to the development of this research plan through informal discussions with working group members. However, the Commission gratefully acknowledges the invaluable input of the working group members and their colleagues throughout the digestive disease research community.

Research on the Basic Biology of the Digestive System

Chair: Richard S. Blumberg, MD, Brigham and Women’s Hospital Vice Chair: Eugene B. Chang, MD, University of Chicago

Hannah Carey, PhD, University of Wisconsin School of Nicholas Davidson, MD, Washington University School of Medicine Marshall Montrose, PhD, University of Cincinnati Chung Owyang, MD, Medical Center Abigail Salyers, PhD, University of Illinois at Urbana-Champaign Ramesh Shivdasani, MD, PhD, Dana Farber Cancer Institute Warren Strober, MD, National Institute of Allergy and Infectious Diseases

Functional Gastrointestinal Disorders and Motility Disorders

Chair: Kenton M. Sanders, PhD, University of Nevada School of Medicine Vice Chair: Nancy J. Norton, BS, International Foundation for Functional Gastrointestinal Disorders

Michael Camilleri, MD, Mayo Clinic College of Medicine Carlo DiLorenzo, MD, Columbus Children’s Hospital Douglas Drossman, MD, University of North Carolina at Chapel Hill Gerald F. Gebhart, PhD, University of Pittsburgh Allen Mangel, MD, PhD, Research Triangle Institute Emeran Mayer, MD, University of California, Los Angeles Henry P. Parkman, MD, Temple University School of Medicine Jack D. Wood, PhD, Ohio State University College of Medicine

Infections of the Gastrointestinal Tract

Chair: Mitchell B. Cohen, MD, Cincinnati Children’s Hospital Medical Center Vice Chair: Richard S. Blumberg, MD, Brigham and Women’s Hospital

Mary K. Estes, PhD, Baylor College of Medicine Alessio Fasano, MD, University of Maryland School of Medicine Richard Fedorak, MD, FRCPC, University of Alberta James B. Kaper, PhD, University of Maryland Cynthia Sears, MD, The Johns Hopkins University School of Medicine Phillip I. Tarr, MD, Washington University School of Medicine

216 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Cancers of the Digestive System

Chair: John M. Carethers, MD, University of California, San Diego Vice Chair: Robert S. Sandler, MD, MPH, University of North Carolina at Chapel Hill

C. Richard Boland, MD, Baylor University Medical Center Raymond DuBois, MD, PhD, Vanderbilt University Medical Center Scott Kern, MD, The Johns Hopkins University Medical Institutions , MD, PhD, University of Michigan Richard M. Peek, Jr., MD, Vanderbilt University School of Medicine Brian Reid, MD, PhD, Fred Hutchinson Cancer Research Center Anil Rustgi, MD, University of Pennsylvania David Whitcomb, MD, University of Pittsburgh School of Medicine Kenneth Wang, MD, Mayo Clinic Vincent Yang, MD, PhD, Emory University School of Medicine

Inflammatory Bowel Diseases

Chair: Daniel K. Podolsky, MD, UT Southwestern Medical Center Vice Chair: Eugene B. Chang, MD, University of Chicago

Brian Feagan, MD, Robarts Research Institute Jeffrey Gordon, MD, Washington University School of Medicine Richard Grand, MD, Children’s Hospital, Boston Jerome I. Rotter, MD, Cedars-Sinai Medical Center William Sandborn, MD, Mayo Clinic R. Balfour Sartor, MD, University of North Carolina at Chapel Hill William F. Stenson, MD, Washington University School of Medicine Stephan Targan, MD, Cedars-Sinai Medical Center; David Geffen School of Medicine at the University of California, Los Angeles

Intestinal Failure and Regeneration, Nutritional Disorders and Support, Surgically Modified Gut, and Transplantation

Chair: Barbara L. Bass, MD, FACS, The Methodist Hospital, Houston Vice Chair: Margaret M. Heitkemper, RN, PhD, University of Washington

Alan Buchman, MD, MSPH, Northwestern University Jeffrey Matthews, MD, University of Chicago Medical Center Denise M. Ney, PhD, RD, University of Wisconsin-Madison William Oh, MD, Women and Infants’ Hospital, Providence Stephen J.D. O’Keefe, MD, University of Pittsburgh Medical College Malcolm K. Robinson, MD, Brigham and Women’s Hospital Robert J. Shulman, MD, Baylor College of Medicine Debra L. Sudan, MD, University of Nebraska Medical Center Brad Warner, MD, Washington University School of Medicine

APPENDIX 2: Rosters of the National Commission on Digestive Diseases and Its Working Groups 217 Diseases of the Oropharynx and Esophagus

Chair: Pankaj J. Pasricha, MD, Stanford University School of Medicine Vice Chair: David A. Lieberman, MD, Oregon Health and Science University

Piero Biancani, PhD, Liver Research Center, Brown Amitabh Chak, MD, Case Western Reserve University Glenn Furuta, MD, Harvard University Medical School John G. Hunter, MD, Oregon Health and Science University Peter Kahrilas, MD, Northwestern University, Feinberg School of Medicine Roy Orlando, MD, Tulane University Medical Center Nicholas Shaheen, MD, MPH, University of North Carolina Reza Shaker, MD, Froedtert Memorial Hospital Stuart Spechler, MD, Dallas VA Medical Center

Diseases of the Stomach and Small Intestine

Chair: Eugene B. Chang, MD, University of Chicago Vice Chair: Maurice A. Cerulli, MD, New York Methodist Hospital

Mark Donowitz, MD, The Johns Hopkins University School of Medicine John S. Fordtran, MD, Baylor University Medical Center Peter H. R. Green, MD, Columbia University, College of Physicians & Surgeons Martin F. Kagnoff, MD, University of California, San Diego Loren A. Laine, MD, University of Southern California Juanita L. Merchant, MD, PhD, University of Michigan Richard M. Peek, Jr., MD, Vanderbilt University School of Medicine Eric Sibley, MD, PhD, Stanford University School of Medicine W. Allan Walker, MD, Massachusetts General Hospital for Children, Harvard Medical School Ernest M. Wright, DSc, PhD, David Geffen School of Medicine, University of California, Los Angeles

Diseases of the Colon and Rectum

Chair: Joanne A. P. Wilson, MD, Duke University Medical Center Vice Chair: Nancy J. Norton, BS, International Foundation for Functional Gastrointestinal Disorders

Lawrence J. Brandt, MD, Albert Einstein College of Medicine Lawrence Samuel Friedman, MD, Massachusetts General Hospital, Newton-Wellesley Hospital Matthew B. Grisham, PhD, Louisiana State University Health Sciences Center J. Thomas Lamont, MD, Beth Israel Deaconess Medical Center; Harvard Medical School Ann Lowry, MD, FACS, University of Minnesota Medical School Jeffrey Matthews, MD, University of Chicago Medical Center

218 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Diseases of the Pancreas

Chair: Jane M. Holt, National Pancreas Foundation Vice Chair: Pankaj J. Pasricha, MD, Stanford University School of Medicine

Peter A. Banks, MD, Harvard Medical School; Brigham and Women’s Hospital Suresh T. Chari, MD, Mayo Clinic College of Medicine Peter Durie, MD, FRCPC, University of Toronto, The Hospital for Sick Children Fred S. Gorelick, MD, School of Medicine Robert H. Hawes, MD, Medical University of South Carolina Richard A. Kozarek, MD, FASGE, University of Washington School of Medicine, Virginia Mason Medical Center Albert Lowenfels, MD, New York Medical College Michael G. Sarr, MD, Mayo Clinic College of Medicine Ashok K. Saluja, PhD, University of Minnesota Medical School David Whitcomb, MD, PhD, University of Pittsburgh School of Medicine

Diseases of the Liver and Biliary System

Chair: Bruce R. Bacon, MD, St. Louis University School of Medicine Vice Chair: Maurice A. Cerulli, MD, New York Methodist Hospital

Montgomery Bissell, MD, University of California, San Francisco Gregory Gores, MD, Mayo Clinic Ronald Sokol, MD, University of Colorado School of Medicine & Children’s Hospital Gyongyi Szabo, MD, PhD, University of Massachusetts Medical School David Thomas, MD, MPH, The Johns Hopkins University School of Medicine John M. Vierling, MD, FACP, Baylor College of Medicine

Bioengineering, Biotechnology, and Imaging

Chair: Barbara L. Bass, MD, FACS, The Methodist Hospital, Houston Vice Chair: David A. Lieberman, MD, Oregon Health and Science University

Stephen F. Badylak, DVM, PhD, MD, University of Pittsburgh Yuman Fong, MD, Memorial Sloan-Kettering Cancer Center Blair S. Lewis, MD, Mount Sinai School of Medicine King C. Li, MD, FRCPC, The Methodist Hospital Research Institute, Houston Norman S. Nishioka, MD, Harvard Medical School Stuart Sherman, MD, Indiana University Medical Center Lee Swanstrom, MD, Oregon Health and Science University

APPENDIX 2: Rosters of the National Commission on Digestive Diseases and Its Working Groups 219 APPENDIX 3: References for Statistical and Epidemiologic Data

Everhart JE, editor. (2008) The burden of digestive diseases in the United States. U.S. Department of Health and Human Services, National Institutes of Health, Public Health Service, National Institute of Diabetes and Digestive and Kidney Diseases. Washington, DC: U.S. Government Printing Office.NIH Publication No. 09-6443.

Garthright WE, Archer DL, Kvenberg JE. (1988) Estimates of incidence and costs of intestinal infectious diseases in the United States. Public Health Rep. 103:107-115.

Jemal A, Siegel R, Ward E, Hao Y, Xu J, Taylor M, Thun MJ. (2008) Cancer statistics, 2008. CA Cancer J Clin. 58:71-96.

Sandler RS, Everhart JE, Donowitz M, Adams E, Cronin K, Goodman C, Gemmen E, Shah S, Avdic A, Rubin R. (2002) The burden of selected digestive diseases in the United States. Gastroenterology. 122:1500-1511.

220 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases APPENDIX 4: Abbreviations and Acronyms

5-ASA 5-aminosalicylic acid 5HT 5-hydroxytryptamine ABCA1 ATP-binding cassette, subfamily A, member 1 ABCG5/G8 ATP-binding cassette transporters G5 and G8 ACTH adrenocorticotropic hormone AIDS acquired immunodeficiency syndrome AIEC adherent invasive E. coli AIH autoimmune hepatitis AIP autoimmune pancreatitis ALADIN alacrima-achalasia-adrenal insufficiency neurologic disorder protein AMP adenosine monophosphate APC adenomatosis polyposis coli APJ apical junctional complex ApoB apolipoprotein B ApoE apolipoprotein E APRIL a proliferation inducing ligand ATG16L1 ATG16 autophagy related 16-like 1 protein BAFF B cell-activating factor of the tumor necrosis factor family BMP bone morphogenic protein BRCA2 breast cancer type 2 susceptibility protein CCK CCR3 chemokine receptor 3 CD Crohn’s disease CD1/CD25/CD40 cluster of differentiation molecules CDX2 caudal-related homeobox 2 CF cystic fibrosis CFTR cystic fibrosis transmembrane conductance regulator CI colonic ischemia CIMP CpG island methylator phenotype CNS central nervous system COX cyclooxygenase CRF corticotropin-releasing factor CRH corticotropin-releasing hormone CT computed tomography

APPENDIX 4: Abbreviations and Acronyms 221 DC dendritic cells DDICC Digestive Diseases Interagency Coordinating Committee DDLT deceased donor liver transplant DGAT diacylglycerol acetyltransferase DHHS U.S. Department of Health and Human Services DNA deoxyribonucleic acid EAEC enteroaggregative E. coli EGID eosinophilic gastrointestinal disorders EGJ esophagogastric junction ENS enteric nervous system EPEC enteropathogenic E. coli ER endoplasmic reticulum ERCP endoscopic retrograde cholangio-pancreatography EUS endoscopic ultrasound FABP fatty acid binding protein FAP familial adenomatous polyposis FATP fatty acid transport protein FDA U.S. Food and Drug Administration FDG-PET 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography FGF fibroblast growth factor FIC Fogarty International Center fMRI functional magnetic resonance imaging FoxP3 forkhead box P3 transcription factor FXR farnesoid X receptor GABAB gamma-aminobutyric acid B receptor GERD gastroesophageal reflux disease Gfi growth factor independence protein GI gastrointestinal GIP glucose-dependent insulinotropic polypeptide GIST gastrointestinal stromal tumor GLP-2 glucagon-like peptide-2 HBV hepatitis B virus HCC hepatocellular carcinoma HCV hepatitis C virus HDL high-density HEV hepatitis E virus HFE hemochromatosis gene HIV human immunodeficiency virus HLA human leukocyte antigen HNPCC hereditary nonpolyposis colorectal cancer hPEPT1 human

222 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases IBD inflammatory bowel diseases IBS irritable bowel syndrome ICC interstitial cells of Cajal ICD International Classification of Diseases IgA IgG immunoglobulin G IGF-1 insulin-like growth factor-1 IL interleukin Insig-1 insulin-induced gene 1 IPMN intraductal papillary mucinous neoplasm ISC intestinal stem cell LDLT living donor liver transplant LES lower esophageal sphincter Lgr5 leucine-rich repeat-containing G-protein coupled receptor 5 LRR leucine-rich repeat LXR liver X receptor MAdCAM-1 mucosal addressin cell molecule 1 Math-1 mouse atonal homolog 1 MALT mucosa associated lymphoid tissue MCN mucinous cystic neoplasm MCT monocarboxylate transporter Mdr2 multiple drug resistance 2 MELD Model for End-Stage Liver Disease MEN 1 multiple endocrine neoplasia type 1 MGAT mannoside acetylglucosaminyltransferase MLCK myosin light chain kinase MMR mismatch repair MRI magnetic resonance imaging MRP2 multidrug resistance-associated protein family MSC mesenchymal stem cell MYH Mut Y homolog NASH non-alcoholic steatohepatitis NCCAM National Center for Complementary and Alternative Medicine NCI National Cancer Institute NCMHD National Center on Minority Health and Health Disparities NCRR National Center for Research Resources NEC necrotizing enterocolitis NERD non-erosive reflux disease NF-κB Nuclear Factor kappa-B NHGRI National Human Genome Research Institute NHLBI National Heart, Lung, and Blood Institute

APPENDIX 4: Abbreviations and Acronyms 223 NIA National Institute on Aging NIAAA National Institute on Alcohol Abuse and Alcoholism NIAID National Institute of Allergy and Infectious Diseases NIBIB National Institute of Biomedical Imaging and Bioengineering NICHD Eunice Kennedy Shriver National Institute of Child Health and Human Development NIDA National Institute on Drug Abuse NIDCR National Institute of Dental and Craniofacial Research NIDDK National Institute of Diabetes and Digestive and Kidney Diseases NIEHS National Institute of Environmental Health Sciences NIH National Institutes of Health NIMH National Institute of Mental Health NINDS National Institute of Neurological Disorders and Stroke NINR National Institute of Nursing Research NK natural killer NKT natural killer T cell NO nitric oxide NOTES natural orifice transluminal endoscopic surgery NPC1L1 Niemann-Pick C1 Like 1 protein NSAID non-steroidal anti-inflammatory drug NSC neural stem cell OD NIH Office of the Director OPASI Office of Portfolio Analysis and Strategic Initiatives ORS oral rehydration solution PanIN pancreatic intraepithelial neoplasia PBC primary biliary cirrhosis PCR polymerase chain reaction PDC-E2 pyruvate dehydrogenase complex-E2 PDGFRA platelet-derived growth factor receptor, alpha polypeptide PELD Pediatric End-Stage Liver Disease PET positron emission tomography PN parenteral nutrition PPAR peroxisome proliferator-activated receptor PPI proton pump inhibitor PSC primary sclerosing cholangitis PTEN phosphatase and tensin homolog PUD peptic ulcer disease PYY peptide YY RAR retinoic acid receptor rDNA ribosomal deoxyribonucleic acid RNA ribonucleic acid Runx3 runt-related transcription factor 3

224 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases RV rotavirus SBP spontaneous bacterial peritonitis SBS short bowel syndrome Scap SREBP cleavage-activating protein SCFA short chain fatty acids SERT serotonin reuptake transporter siRNA small interfering ribonucleic acid SNP single nucleotide polymorphism SPECT single photon emission computed tomography SPINK1 serine protease inhibitor, Kazal type 1 SQUID superconducting quantum interference device SREBP sterol-regulatory element binding protein STAT3 signal transducer and activator of transcription 3 STEP serial transverse enteroplasty TE/RM tissue engineering/regenerative medicine TFF trefoil factor TGF transforming growth factor TIMP tissue inhibitor of metalloproteinases TLR Toll-like receptor TNF tumor necrosis factor TRPV1 transient receptor potential vanilloid 1 TSLP thymic stromal lymphopoietin UC ulcerative colitis VEGF vascular endothelial growth factor ZES Zollinger-Ellison syndrome

APPENDIX 4: Abbreviations and Acronyms 225 INDEX

A

absorption 3, 5, 13, 20, 25-27, 29-31, 39-42, 104, 108-111, 114, 131-133, 136-137, 141-142, 146, 148, 152, 160, 163, 174, 180, 207, 210 achalasia 21, 55, 119, 122, 221 acquired immunodeficiency syndrome 70, 120, 221 Action Plan for Liver Disease Research 8, 17, 21-22, 169, 171-174, 176-184 adaptation 6, 28, 37, 40-41, 107-110, 112-114, 207 adenocarcinoma 37, 82-84, 90, 119, 122, 162, 170, 190, 209 adenoma 87-88, 92 Agency for Healthcare Research and Quality 2, 16 AIDS (See acquired immunodeficiency syndrome) AIH (See autoimmune hepatitis) Alagille syndrome 179, 211 alcohol 8-9, 13, 17, 119, 159-160, 162-163, 165-166, 170, 176-177, 183, 195, 210-211 allergy or allergic disease 7, 34, 46, 62, 75-76, 120, 122, 124, 126, 129, 131, 134, 138-141, 210 alpha-1-antitrypsin deficiency 173, 179, 211 amebiasis 3, 72 angioectasia 7, 21, 145-147, 150, 154, 210 angiosarcoma 183 animal model 10, 28, 35-37, 39-41, 43-44, 46-47, 53-56, 59-62, 64-65, 73-74, 77-78, 85, 93, 98, 100, 105, 109, 112-113, 123, 125, 132, 134, 136-138, 140-141, 152, 156-157, 161, 166, 173, 178-181, 183-185, 201-202 antibiotic resistance 27, 33, 48, 70, 75 antibiotics 3, 14, 53, 59, 70, 75, 97, 146, 148, 150, 153, 155 anus 13, 82-83, 92, 146-147 appendicitis 8, 13, 21, 145-148, 151-152, 155, 157, 210 appetite 32, 38, 52, 207 asthma 119, 121, 123, 134-135 autoimmune hepatitis 178-179, 211, 221 autoimmunity 8, 14, 21, 45-46, 55, 70, 72-73, 76, 122, 125, 129, 131, 134, 138-141, 159, 162, 164-165, 169-170, 176, 178-180, 182, 197, 210-211, 221 autonomic nervous system 41, 56, 58, 60-62, 64-65, 165, 208

226 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases B

B cell 34-35, 47, 221 bacteria 3, 5, 17, 21, 27, 29-30, 32-33, 39, 44, 48, 54-55, 60, 69-74, 76-77, 85, 88, 98-99, 110-112, 131, 133, 136-137, 139, 146-149, 151-153, 155-156, 163, 176, 182, 184, 210, 225 bariatric surgery 6, 21, 38, 107, 109, 112-114, 209 Barrett’s esophagus 3, 7, 21, 37, 90, 117, 119, 121-122, 124-126, 189-190, 210 behavior 1, 5, 14, 18, 38, 44-45, 51, 53, 63, 65, 76, 87-89, 196, 200, 202 Bianchi procedure 3, 110 bile 13, 39, 172, 174, 178-179, 184, 211 bile duct 13, 82, 96, 160, 170, 176 biliary atresia 17, 72, 179-180, 184, 211 biliary disease 8-9, 17, 169-171 biliary system 2, 8, 11, 13, 22, 26, 28, 36, 83, 169-172, 176, 178, 188, 204, 211 bioengineering 2, 9, 16, 22, 187, 212 bioinformatics 48-49, 78, 104 biomarker 6, 10, 32, 38, 40-41, 57, 61, 65-66, 76, 81, 83, 87, 89-92, 100, 103, 113, 124-125, 139-140, 142, 154, 166, 173, 179-180, 182-185, 199, 209, 212 biotechnology 2, 9, 22, 142, 156, 187, 212 bleeding 3, 4, 130, 132, 147, 150-151, 153, 190, 195 bloating 14, 52-53, 60, 147 brain 5, 25-27, 29, 31, 38, 43, 44, 51-61, 64-66, 120, 208

C

C. difficile (See Clostridium difficile) cancer 2-9, 13-14, 20-22, 25-28, 32, 35-37, 43, 45, 47, 55, 80-93, 95-96, 104, 117, 119, 121-122, 126, 130, 132, 135-136, 141, 145-147, 155, 159-161, 164, 166, 169-170, 176, 178, 180-181, 183-184, 188-190, 195, 197-198, 207, 209-210, 221-222 (See also tumor) carcinoma 82, 87, 90-92, 183, 209, 212, 222 CD (See Crohn’s disease) CDC (See Centers for Disease Control and Prevention) celiac disease 7, 13-14, 21, 27, 46, 92, 129-131, 133-134, 137-139, 141-142, 197, 210 Centers for Disease Control and Prevention 2, 17 central nervous system 43, 54, 56-62, 64-65, 73, 118, 123, 125-126, 196, 208, 221 CF (See cystic fibrosis) chemokine 33-34, 45-46, 134, 161, 221 chest pain 119-120, 122-123, 125 cholangiocarcinoma 183-184, 212 cholecystectomy 170, 184, 189 cholecystitis 184 cholesterol 29, 39, 171-172, 174, 184 chronic intestinal pseudoobstruction 13, 21, 52, 55-56, 63 CI (See colonic ischemia) cirrhosis 9, 169-170, 172, 175, 177-178, 182-183, 211-212, 224 Clinical and Translational Science Award 200

INDEX 227 Clostridium difficile 21, 27, 70-72, 75 146, 153 CNS (See central nervous system) colitis 21, 29, 38, 72, 75, 96, 98, 100, 137, 146-148, 151, 154-155, 157, 225 colon 2, 7-8, 13, 21, 27, 32-33, 44-46, 48, 56, 80, 82-83, 85-87, 91, 96-97, 130, 133, 137, 144-157, 186, 188, 190, 209, 210, 221 (See also large intestine) colon cancer (See colorectal cancer) colonic ischemia 8, 21, 145-147, 150-151, 154, 211, 221 colorectal cancer 3, 6, 9, 14, 20, 27-28, 32, 36, 45, 80-83, 85-88, 91-92, 146, 186, 189-190, 195, 207, 209, 222 congenital chloridorrhea 132 congenital hepatic fibrosis 180, 211 constipation 5, 14, 51-53, 57, 60-61, 63-64, 146-147, 151-153, 155, 195 corticotropin-releasing factor 31, 42, 53-55, 221 CRF (See corticotropin-releasing factor) Crigler-Najjar syndrome 173 Crohn’s disease 4, 13, 21, 72, 94, 96-98, 108, 112, 137, 150, 154, 190, 221 cystic fibrosis 8, 21, 159-162, 165, 180-181, 211, 221 cytokine 33, 35, 38, 45, 47, 60, 66, 84-85, 97-100, 113, 120, 138, 151, 161, 163-164, 191

D

D-glucose/D-galactose malabsorption 132 DC (See ) DDICC (See Digestive Diseases Interagency Coordinating Committee) dendritic cell 33-35, 45-46, 48, 76, 99, 222 Department of Agriculture 2, 17 Department of Defense 2, 16 Department of Veterans Affairs 2, 17 development, biological 2, 5-6, 8, 10, 15, 20, 25-26, 28, 30, 34-37, 40-41, 44, 46-47, 49, 53, 55-56, 58, 76-77, 95, 104, 109, 111, 120, 131, 137-139, 142, 169, 173, 179-180, 196, 198, 207-209, 211-212 diabetes 5, 27, 30, 32, 38-41, 51, 55-56, 61, 75, 97, 119, 125, 134, 138, 160-161, 163, 177, 208 diarrhea 3, 7, 13-14, 21, 26, 52-54, 60-61, 64, 68, 70-72, 74-77, 96, 108, 129-134, 136-137, 141-142, 146-148, 152-153, 195, 197, 210 diet 29, 32, 38-39, 44, 60, 62, 73, 77, 91, 108-109, 113-114, 120, 131, 133, 139, 147-149, 151-153, 155, 157, 184, 197 differentiation 5-7, 25, 28, 30, 32-39, 42, 45-47, 84, 102, 107-108, 110, 112, 121, 137, 148, 192, 208- 209, 221 Digestive Diseases Interagency Coordinating Committee 2, 11, 16-18, 204, 222 diverticular disease 8, 14, 21, 144-147, 149-150, 153, 156-157, 210 drug-induced liver disease 8, 22, 169, 177-178, 180, 182 dysphagia 21, 118-119, 122

228 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases E

E. coli (See Escherichia coli) education 1, 10-11, 17-18, 23, 63, 89, 105, 135, 142, 154-155, 201-204, 213 EGID (See eosinophilic gastrointestinal disorder) end-stage liver disease 170, 175, 180-182, 223-224 endocrinology 21 endoderm 26, 28, 36, 207 endoscopic ultrasound 3, 85-86, 162, 190, 222 endoscopy 3-4, 9, 21, 85-86, 90, 92, 96, 103, 113, 115, 121, 123, 125-126, 141, 160, 162, 164-165, 167, 187-193, 195, 200, 211-212, 222, 224 ENS (See enteric nervous system) enteral nutrition 7, 107, 109, 111, 114, 131 enteric nervous system 5, 25, 27, 31, 41-44, 48, 51-52, 54-56, 59, 61, 65, 103, 118, 207-208, 222 enterocyte 29, 37, 39, 109, 110, 136 enteroendocrine cell 27, 31, 42, 60, 62, 102, 132, 137 environment 1, 7, 10, 18, 26-27, 29, 42, 46, 58, 62, 64-65, 71-72, 74, 76, 88, 90-91, 97, 100-102, 111, 124-126, 129, 139, 154, 164-165, 177, 179, 189, 192, 197, 199, 209, 211 eosinophilic esophagitis 7, 13, 21, 116-117, 120, 122, 124-126, 210 eosinophilic gastrointestinal disorder 7, 21, 129, 131, 137, 140-141, 210, 222 epidemiology 1, 6, 10, 17-18, 22, 54, 56, 62, 69, 72, 74, 78, 82, 92, 124-125, 135, 137, 140, 147, 165- 166, 199-200, 208, 210-212 epigenetics 30, 84, 88-90, 121, 148, 197 Escherichia coli 21, 68, 71, 78, 98, 147, 221-222 esophageal cancer 3, 6-7, 81-85, 88, 90, 117, 119, 209 esophagus 2, 3, 7, 13, 21, 37, 61, 82, 85, 90, 116-126, 170, 188, 190, 192, 209-210 Eunice Kennedy Shriver National Institute of Child Health and Human Development 15-16, 224 EUS (See endoscopic ultrasound)

F fatty liver disease 9, 22, 111, 169-170, 177, 183, 211 (See also hepatic steatosis) FDA (See Food and Drug Administration) fecal incontinence 8, 17, 21, 52, 57-58, 63, 145-147, 150-151, 154-155, 157, 210 fibrolamellar carcinoma 183 fibrosis 8, 21, 99-100, 103, 151, 159-161, 163-165, 172-173, 177, 180-181, 211, 221 FIC (See Fogarty International Center) fissure 146-147, 151 fistula 8, 21, 145-147, 150, 154, 190 Fogarty International Center 15-16, 222 Food and Drug Administration 2, 16, 185, 198, 200, 222 functional dyspepsia 5, 21, 43, 51-52, 54, 119, 130, 141 functional gastrointestinal disorders 1-2, 5, 9, 14, 21, 31, 43, 51-66, 70, 119, 146, 195-196, 208

INDEX 229 G

gallbladder 13, 82, 170, 174, 184, 189 gallstone 8, 21, 159-160, 163, 169-170, 184, 212 Gardner’s syndrome 88 gastric cancer 6, 37, 81-85, 88, 90-91, 130, 132, 135-136, 141, 209-210 gastrinoma 130, 132, 136, 141 gastroenteritis 54, 73, 121, 131, 141 gastroesophageal reflux disease 5, 7, 13, 21, 51-52, 88, 117-121, 123-126, 135, 209, 222 gastrointestinal stromal tumor 83, 87, 92, 146, 188, 191, 222 gastrointestinal tract 2-3, 5-7, 9, 11, 13, 21, 25-28, 32, 36, 38, 41, 43, 47-48, 51, 54-66, 69, 75, 77, 81- 82, 87-88, 92-93, 95-96, 103-104, 107-109, 111, 117-118, 122-123, 126, 129-134, 140, 146-147, 153-154, 187-193, 197-198, 204, 207-209 gastroparesis 5, 21, 51-52, 56, 59-60, 63 genetics 1-3, 5-8, 18, 27-29, 31, 33, 36, 38-40, 42-43, 47, 49, 51, 53-58, 61-62, 64-66, 70-73, 75, 77, 81, 83-86, 88-91, 94-95, 97-98, 100-102, 104, 125-126, 129, 131-132, 134, 136, 138-141, 148-149, 153, 155, 159, 161-166, 169, 171, 173, 179-181, 183-185, 196-199, 201-202, 209-212 genomics 32, 43-44, 48-49, 64-65, 73-74, 84, 89, 91-92, 98-99, 104, 142, 146, 171, 202 genotype 44, 60, 62, 65, 74, 100-101, 104, 132, 208 GERD (See gastroesophageal reflux disease) ghrelin 30, 54, 112 GIP (See glucose-dependent insulinotropic polypeptide) GIST (See gastrointestinal stromal tumor) gliadin 131 glial cell 31, 41-42, 58, 64, 149 GLP-1 (See glucagon-like peptide-1) GLP-2 (See glucagon-like peptide-2) glucagon-like peptide-1 32 glucagon-like peptide-2 29, 37, 109-110, 222 glucose-dependent insulinotropic polypeptide 32, 222 gluten 131, 133, 138 growth factor 29, 37, 84, 86, 108-110, 112-113, 134, 148, 152, 174, 182, 184, 191, 222-225 Guillain-Barre syndrome 72

H

H. pylori (See Helicobacter pylori) HapMap 39 HCC (See hepatocellular carcinoma) health disparities 1, 6, 14, 18, 81, 88, 92, 176, 200, 209 Health Resources and Services Administration 2, 17 heartburn 3, 118, 120-122, 195 Helicobacter pylori 3, 7, 9, 13-14, 70, 82, 85, 92, 128-130, 132, 135, 141-142, 195, 197, 210 helminth 5, 69, 73, 76 hemochromatosis 179-181, 211, 222 hemophilia 173

0 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases INDEX hemorrhoid 8, 145-147, 150-151, 154 hepatic steatosis 8-9, 13, 169, 176-177, 195, 223 (See also fatty liver disease) hepatitis 3-4, 8-9, 13-14, 17, 21, 88, 168-170, 174-183, 195, 197, 199, 211, 221-223 hepatoblastoma 183 hepatocellular carcinoma 183-184, 212, 222 hepatocyte 168, 171-173, 178, 180, 191, 198 hereditary nonpolyposis colorectal cancer 86, 222 hernia 109, 121, 124 Hirschsprung’s disease 13, 52, 55-56 HIV (See human immunodeficiency virus) HNPCC (See hereditary nonpolyposis colorectal cancer) hookworm 3, 72 hormone 6, 26-32, 37-38, 42-45, 53-55, 58, 60, 84, 107, 109-110, 112-114, 122, 130, 165, 174, 221 Human Genome Project 171 human immunodeficiency virus 8, 27, 47, 120, 169, 176-177, 211, 222 Human Microbiome Project 19, 48, 78, 104, 156, 197 human papilloma virus 92 hypersensitivity 52-53, 56, 59, 62-63, 119, 123, 125-126, 139, 149-150

I

IBD (See inflammatory bowel diseases) IBS (See irritable bowel syndrome) ICC (See interstitial cells of Cajal) imaging 2-4, 9-10, 21, 41, 43-44, 56-57, 62, 64-66, 77, 85-87, 90-92, 100, 103, 120, 122-123, 126, 137, 141, 156, 160-163, 166, 183, 186-193, 195, 198-200, 202, 212, 222-223 infections 2-3, 5, 13-14, 21, 27, 45, 47, 54, 60-61, 69-78, 88, 90, 92, 97, 109, 113, 120-121, 130-132, 134, 141, 146-148, 152-153, 155, 174-176, 182, 195, 197, 208 infectious agents 5, 13, 69, 70, 74, 77, 130-131, 197 (See also infections) infectious diseases 3, 5-6, 14, 25-26, 34, 45, 69, 70, 72, 77, 121, 130, 133, 175, 197, 199 (See also infections) inflammation 2-7, 13-14, 21, 26, 28-29, 31, 33-34, 38-39, 41-42, 45-47, 51, 53-56, 58-60, 70, 72, 76, 82, 85, 87-89, 91, 95-105, 108, 117, 120, 122-124, 129-136, 138-140, 142, 146-148, 150, 152-153, 160-164, 172-173, 177-179, 188, 190, 192, 195, 197, 207-212, 223-224 inflammatory bowel diseases 2-3, 6, 13-14, 21, 26-27, 32-34, 37, 39, 45, 55, 70, 72, 76-77, 88, 95-105, 130, 133-134, 141, 146, 150, 153-154, 179, 192, 195-197, 209, 223 injury 3, 7-8, 28, 32, 37, 39-40, 53, 71, 73, 99-100, 102-104, 107-108, 112, 120-121, 124, 129, 131-132, 134- 136, 138-139, 141, 145-148, 150-152, 154-155, 161, 163-164, 170, 172-179, 182-183, 192, 209-212 interstitial cells of Cajal 5, 31, 42-44, 50-51, 56-58, 60, 63-64, 87, 149, 223 intestinal crypt 2, 24, 26, 28, 30, 33, 36, 70, 106, 108, 186 intestinal failure 2, 6, 21, 26, 37, 107-115, 189, 209 intestinal lengthening 3, 110 intestinal stem cell 35, 102, 108, 111-112, 189, 223 intraductal papillary mucinous neoplasm 161-162, 166, 223 IPMN (See intraductal papillary mucinous neoplasm) iron 31, 39-40, 180-181 irritable bowel syndrome 5, 13, 21, 26, 31, 42-45, 51-57, 59, 70, 72, 76-77, 119, 147, 150, 156, 223 ISC (See intestinal stem cell)

INDEX 231 J

jaundice 174, 195

L

lactase deficiency 132, 137 large intestine 13, 34, 54, 96, 146 (See also colon) LES (See lower esophageal sphincter) liver 2, 8-9, 11, 13, 17-18, 21-22, 26, 28, 31, 36, 38, 47, 82-84, 96-97, 108-111, 161, 168-185, 188-189, 191, 195, 197-199, 204, 207, 211-212, 222-224 liver cancer 8, 21, 82-83, 169-170, 180-181, 183-184, 212 liver failure 17, 108-109, 173, 176-179, 181-183, 189, 195, 212 loan repayment 10, 202-203 lower esophageal sphincter 52, 119, 121-122, 223 lymphoma 83, 92, 176 Lynch syndrome 86, 88

M

magnetic resonance imaging 48, 57, 60-61, 64, 86, 160, 188, 200, 202, 222-223 malabsorption 7, 26, 40, 104, 110, 129-133, 137, 141-142, 160, 163, 210 malignancy (See cancer; tumor) malnutrition 70, 75, 108, 131, 146 (See also nutrition) manometry 57 MCN (See mucinous cystic neoplasm) megacolon 52 MELD (See Model for End-Stage Liver Disease) Menke’s disease 132 mesenchymal stem cell 35, 48, 223 metabolic syndrome 26, 38, 45, 177 metabolism 5, 21, 25-26, 29-30, 38-39, 156, 172, 174, 180, 207, 211 metabolomics 38, 77, 156, 198 microbiology 21, 26-27, 32, 44, 78, 197, 199 microbiome 26, 32, 44, 48, 60, 76-78, 100-102, 104-105, 197, 209 microflora 3, 5-8, 10, 25-27, 32-33, 35, 44-48, 51, 54-55, 60-62, 69-71, 73, 75-78, 88, 90, 95, 97-104, 111, 114, 133-134, 138-139, 145-146, 148-149, 151-153, 156, 208-210 mitochondrial hepatopathies 179, 211 Model for End-Stage Liver Disease 182, 223 motility, normal 5, 20, 25-27, 29, 31, 41-43, 50-66, 114, 122, 137, 207-208 motility disorders 2, 5, 7, 21, 27, 29, 31, 38, 42-43, 51-66, 117, 119, 124-126, 134, 146, 208 MRI (See magnetic resonance imaging) MSC (See mesenchymal stem cell) mucinous cystic neoplasm 161-162, 223 mucosa 4-6, 27, 33-34, 46-47, 51, 54, 61, 85, 95, 103-105, 121, 128, 131-132, 136, 138, 146, 148, 155- 156, 188-190, 210, 223

232 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases mucosal immunity 5-6, 20, 25, 27, 33-35, 45-47, 54-55, 59, 72, 77, 95, 99, 102, 131, 134, 139, 142, 197, 208-209 multiple endocrine neoplasia type 2B 55 muscularis 43, 52, 58, 64, 208

N

NASH (See non-alcoholic steatohepatitis) National Cancer Institute 15-16, 18, 223 National Center for Complementary and Alternative Medicine 15-16, 223 National Center for Research Resources 15-16, 200, 223 National Center on Minority Health and Health Disparities 15-16, 223 National Commission on Digestive Diseases 1-2, 4-9, 11, 15, 17-22, 25-26, 51, 69, 81, 95, 107, 109, 117, 129, 145, 159, 169, 171, 187,195-196, 204-205, 207, 214-219, 226 National Digestive Diseases Information Clearinghouse 2, 17 National Heart, Lung, and Blood Institute 15-16, 223 National Human Genome Research Institute 15-16, 223 National Institute of Allergy and Infectious Diseases 15-16, 224 National Institute of Biomedical Imaging and Bioengineering 15-16, 224 National Institute of Dental and Craniofacial Research 15-16, 224 National Institute of Diabetes and Digestive and Kidney Diseases 1-2, 15-19, 194, 220, 224, 226 National Institute of Environmental Health Sciences 15-16, 224 National Institute of Mental Health 15-16, 224 National Institute of Neurological Disorders and Stroke 15-16, 224 National Institute of Nursing Research 15-16, 224 National Institute on Aging 15-16, 224 National Institute on Alcohol Abuse and Alcoholism 15-16, 224 National Institute on Drug Abuse 15-16, 224 National Institutes of Health 1-2, 4, 8-9, 11, 14-22, 26, 48, 78, 104, 109, 142, 156, 169, 171, 194-198, 200-205, 207, 220, 224 natural history 10, 22, 52, 87-88, 91-92, 100, 121, 123-124, 126, 140-142, 154, 162-163, 165-166, 179, 199, 209-210, 212 natural orifice transluminal endoscopic surgery 189, 224 nausea 13, 52-53, 59-61, 147, 208 NCCAM (See National Center for Complementary and Alternative Medicine) NCI (See National Cancer Institute) NCMHD (See National Center on Minority Health and Health Disparities) NCRR (See National Center for Research Resources) NEC (See necrotizing enterocolitis) necrotizing enterocolitis 7, 14, 21, 75, 107-109, 111, 114, 129-131, 134, 139-142, 197, 210, 223 neonatal hemochromatosis 179, 211 neonatal hepatitis 179, 211 NERD (See non-erosive reflux disease) neural stem cell 3, 35, 41, 44, 55, 122, 224 neurophysiology 20, 26-27, 31, 39, 41, 121 NHGRI (See National Human Genome Research Institute)

INDEX 233 NHLBI (See National Heart, Lung, and Blood Institute) NIA (See National Institute on Aging) NIAAA (See National Institute on Alcohol Abuse and Alcoholism) NIAID (See National Institute of Allergy and Infectious Diseases) NIBIB (See National Institute of Biomedical Imaging and Bioengineering) NICHD (See Eunice Kennedy Shriver National Institute of Child Health and Human Development) NIDA (See National Institute on Drug Abuse) NIDCR (See National Institute of Dental and Craniofacial Research) NIDDK (See National Institute of Diabetes and Digestive and Kidney Diseases) NIEHS (See National Institute of Environmental Health Sciences) NIH (See National Institutes of Health) NIH Celiac Disease Awareness Campaign 142 NIH Loan Repayment Programs for Clinical and Pediatric Research 202-203 NIH Nutrition Coordinating Committee 21, 109 NIH Office of the Director 15-16, 19, 224 NIH Roadmap for Medical Research 15-16, 19, 48, 78, 105, 156 NIMH (See National Institute of Mental Health) NINDS (See National Institute of Neurological Disorders and Stroke) NINR (See National Institute of Nursing Research) non-alcoholic steatohepatitis 9, 13, 170, 176-177, 180, 183, 195, 211, 223 non-erosive reflux disease 7, 117, 123, 125, 223 non-steroidal anti-inflammatory drug 3, 7, 13, 87, 129-130, 132, 135-136, 141-142, 210, 224 NOTES (See natural orifice transluminal endoscopic surgery) NSAID (See non-steroidal anti-inflammatory drug) NSC (See neural stem cell) nutrition 2, 4, 6-7, 13, 21, 26-27, 31, 37, 39, 52, 54, 59, 104, 107-109, 111, 113-115, 147, 152-153, 156, 164, 209, 224 (See also malnutrition) nutritional support 7, 21, 107, 109, 114, 209

O

obesity 3, 9, 21, 26-27, 29, 32, 38-41, 43, 45, 54-55, 61, 70, 73, 77, 90, 109, 122, 133, 137, 146, 149, 153, 163, 170, 177, 195, 207 OD (See NIH Office of the Director) oropharynx 2, 7, 21, 117-118, 120, 123, 125, 209

P

pain 5, 8, 13-15, 43, 51-53, 55-56, 58-59, 61-64, 96-97, 119-120, 122-123, 125, 130-131, 147, 151, 159-161, 164-166, 195, 208, 211 pancreas 2-4, 6, 8, 11, 13-14, 21, 26, 28-29, 36-38, 47, 81-83, 85-86, 88, 91, 97, 158-167, 180, 188-190, 195, 197, 204, 207, 209-211 pancreatic cancer 6, 8, 14, 81-83, 85-86, 91, 159-161, 164-166, 209, 211 pancreatic intraepithelial neoplasia 88, 91, 161, 165-166, 211, 224

234 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases pancreatitis 4, 8-9, 13-15, 21, 29, 38, 97, 158-166, 195, 197, 210-211, 221 PanIN (See pancreatic intraepithelial neoplasia) parasite 21, 70, 72, 74, 78 parenteral nutrition 7, 37, 107-111, 113-114, 224 PBC (See primary biliary cirrhosis) Pediatric End-Stage Liver Disease 182, 224 PELD (See Pediatric End-Stage Liver Disease) peptic ulcer disease 3, 7, 21, 70, 128-130, 135, 224 (See also ulcer) perforation 130, 147 peristalsis 41-42, 108, 121 peritonitis 147, 155, 182, 225 PET (See positron emission tomography) pharmacogenomics 62, 101, 135, 197 PN (See parenteral nutrition) polycystic liver disease 180-181, 211 polyposis 86-88, 91-92, 221-222 polyps (See polyposis) porphyria 173, 180-181, 211 portal hypertension 182, 212 positron emission tomography 43, 57, 61, 64, 188, 190-192, 200, 202, 222, 224 PPI (See proton pump inhibitor) prebiotics 17, 45, 75, 77, 114, 150-151, 153, 155, 197 prematurity 7, 107, 109, 111, 114, 117, 119, 130-131, 134, 139-140, 210 primary biliary cirrhosis 178, 211, 224 primary sclerosing cholangitis 178-179, 183-184, 211, 224 probiotics 17, 45, 53, 55, 59, 72, 75, 77-78, 89, 111, 114, 134, 139-140, 142, 150, 153, 155, 197, 209 progressive familial intrahepatic cholestasis 179, 211 proteomics 10, 37-38, 40, 43, 49, 64, 84, 92, 113, 137, 142, 146, 172, 198-199 proton pump inhibitor 119, 121, 135, 224 protozoa 5, 69, 73, 176 PSC (See primary sclerosing cholangitis) pseudoobstruction (See chronic intestinal pseudoobstruction) psychosocial factor 53-54, 56, 63, 65, 119, 199 public health 1, 6, 13-14, 19, 21, 69, 81, 91 PUD (See peptic ulcer disease)

Q quality of life 1-2, 6-8, 13-15, 22, 52, 59, 61, 63, 86, 95, 107, 109-110, 114, 122, 126, 145, 147, 152-154, 159, 165-166, 191, 199

INDEX 235 R

radiation colitis 146-147, 151, 155, 157 radiation injury 8, 28, 89, 145, 151-152, 155, 210 radiation proctitis 13, 21, 113, 151, 155 rectum 2, 8, 13, 21, 61, 82, 96-97, 145-147, 151, 154, 156-157, 188, 190, 210 regeneration 2-3, 5-6, 9, 21, 25, 27, 31-32, 63, 95, 103, 106-109, 111, 114, 146, 148, 152, 163, 173, 183, 187, 189, 191-193, 198, 209, 211-212, 225 registry 10, 65, 110, 114, 126, 141, 166, 193, 199 risk factor 3, 6-9, 14, 17-18, 38, 54, 70, 73, 75, 81, 85-92, 95-98, 101, 117-119, 121-122, 124-126, 130- 132, 134-135, 138-142, 145, 150-151, 153-156, 159-166, 176, 178-179, 181, 183-184, 187, 197, 199, 209-212 (See also genetics) rotavirus 3, 71-73, 225

S

satiety 20, 30, 32, 38, 43, 61, 207 SBS (See short bowel syndrome) scaffold 9, 111-112, 187, 189, 191-192 schistosomiasis 3, 72 scleroderma 119 secretion 5, 8, 13, 20, 25-27, 29-30, 32, 38, 40-42, 48, 51-52, 54, 57, 61, 108, 130, 133, 137, 141-142, 146, 148, 153, 159, 161, 174, 179, 184, 207-208, 211 sepsis 111, 114, 146-147 serial transverse enteroplasty 3, 110, 225 serotonin 29, 31, 38, 53-54, 225 short bowel syndrome 3, 7, 13, 21, 28, 37, 107-110, 112-115, 192, 209, 225 simulation 9, 21, 187, 189, 192, 212 single photon emission computed tomography 57, 225 small bowel (See small intestine) small intestine 2, 4, 7, 13, 21, 24, 34, 60, 63, 68, 70, 82-83, 92, 106, 108-111, 114-115, 129-130, 133, 137, 141-142, 146, 155, 188-190, 192, 197, 210 smooth muscle 5, 31, 41-43, 51, 53, 55-56, 60, 63-64, 118, 121, 149, 174 SPECT (See single photon emission computed tomography) SQUID (See superconducting quantum interference device) stem cell 3, 5, 9-10, 25-28, 31-32, 35-37, 41, 44, 46, 48, 55, 63, 66, 84, 90, 102-103, 106, 108, 110-112, 121-122, 124-126, 132, 164, 173, 187, 189, 191-192, 198, 207, 223-224 stomach 2, 7, 13, 21, 26, 31, 36, 50, 52-53, 70, 82, 90, 109, 129, 130, 135, 141-142, 188-189, 210 stricture 119, 124, 151, 164, 190 stroke 7, 117-118, 123 superconducting quantum interference device 61, 202, 225 surgical technique 3, 63, 181, 187, 191 surgically modified gut 2, 6, 21, 103, 106-115 swallowing disorders 7, 21, 117-120, 123, 125-126 symbiotics 77, 114 systems biology 46, 49, 64, 66, 102-103, 141, 156, 196

236 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases T

T cell 33-35, 45-47, 76, 138, 208, 224 TLR (See Toll-like receptor) TNF (See tumor necrosis factor) Toll-like receptor 33-35, 45-46, 98-99, 134, 139, 148, 152, 225 toxin 17, 32-33, 35, 44-45, 48, 71, 122, 138, 170, 172 training 2, 11, 15-16, 18, 21-22, 63, 189, 192-193, 201-204, 213 transplantation 2, 6-9, 17, 21, 35, 63, 66, 70, 74, 107-111, 113-115, 130, 164, 169-170, 173, 175-183, 197-198, 209, 212, 223-224 transporter 26, 29-30, 38-39, 42, 54, 136-137, 148, 152-153, 171, 180, 184, 221-223, 225 trauma 9, 28, 39, 108, 120, 187, 189, 192 tumor 28, 36, 83-84, 86-87, 89-90, 92, 108, 121, 130, 132, 136, 141, 146-147, 161, 188, 190-192, 222 (See also cancer) tumor necrosis factor 14, 30, 97, 99, 111, 221, 225

U

UC (See ulcerative colitis) ulcer 3, 7, 9, 14, 21, 70, 129-130, 132, 135, 195, 224 (See also peptic ulcer disease) ulcerative colitis 21, 72, 96-97, 154, 225 ultrasound 3, 61, 85, 162, 188, 190, 202, 222

V vaccine 3-6, 8-9, 14, 25-27, 34, 47, 69, 71-72, 74-78, 86, 91, 169-170, 175, 197, 208 villus 26, 28, 36, 68, 70, 108-110, 131 viral hepatitis 3-4, 8-9, 13-14, 17, 21-22, 168-170, 174-176, 180-183, 195, 197, 199, 211 vitamin 34, 108-109, 114, 131, 146, 178 volvulus 108 vomiting 13, 31, 52, 59-61, 120, 131, 147, 208

W weight 3, 7, 29, 38, 43, 96, 107, 109, 111-113, 149, 177 Wilson disease 180, 211 World Health Organization 82, 162

Z

ZES (See Zollinger-Ellison syndrome) Zollinger-Ellison syndrome 130, 132, 136, 141, 225

INDEX 237 ACKNOWLEDGEMENTS

The National Commission on Digestive Diseases gratefully acknowledges all of the working group members (see Appendix 2) and their colleagues in the digestive diseases research and advocacy communities for their input and assistance in developing a comprehensive set of recommendations for the future of digestive diseases research.

Special appreciation is also extended to professional and patient advocacy group members and the general public who attended meetings and submitted suggestions during the public comment period.

238 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases 239 240 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases