Current Role of Immunosuppressants in IBD: Special Lecture Dig Dis 2014;32(suppl 1):96–102 DOI: 10.1159/000367836 Integrating Omics: The Future of IBD? Claudio Fiocchi Department of Gastroenterology and Hepatology, Digestive Disease Institute, and Department of Pathobiology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio , USA Key Words plying personalized medicine and far more effective thera- IBD · Crohn’s disease · Ulcerative colitis · Omes · Omics · pies to individual patients with Crohn’s disease and ulcer- Integrome · Interactome ative colitis. For the practicing gastroenterologist, an omics- based delivery of healthcare may be intimidating, but it must be accepted and implemented if he or she is to provide the Abstract best possible care to IBD patients. © 2014 S. Karger AG, Basel The complexity of IBD is well recognized as are the putative four major components of its pathogenesis, i.e. environment, genetic makeup, gut microbiota and mucosal immune re- sponse. Each of these components is extremely complex on Introduction its own, and at present should be more appropriately defined by the terms ‘exposome’, ‘genome’, ‘microbiome’ and ‘immu- There are still multiple unanswered issues in regard to nome’, respectively, based on the ‘ome’ suffix that refers to a IBD that range from its etiology to the reasons underlying totality of some sort. None of these ‘omes’ is apparently ca- its variable manifestations, the challenge of a precise diag- pable of causing IBD by itself; it is instead the intricate and nosis, the choice of an ideal therapy, the need for surgery, reciprocal interaction among them, through the so-called the threat of cancer and the prediction of the ultimate out- ‘IBD interactome’, that results in the emergence of IBD, or come. There is, however, one single issue where there is more appropriately the ‘IBD integrome’. To deal with and un- general agreement among investigators, physicians and derstand such overwhelming biological complexity, new ap- patients alike – its overwhelming complexity. In fact, both proaches and tools are needed, and these are represented by forms of IBD, Crohn’s disease (CD) and ulcerative colitis ‘omics’, defined as the study of related sets of biological mol- (UC), are prototypical examples of a class of what are en- ecules in a comprehensive fashion, such as genomics, tran- titled complex diseases, which include many other chron- scriptomics, proteomics, metabolomics, and so on. Numer- ic inflammatory and autoimmune disorders such as asth- ous bioinformatics-based tools are available to explore and ma, rheumatoid arthritis, psoriasis, multiple sclerosis, sys- take advantage of the massive amount of information that temic lupus erythematosus and various forms of allergic can be generated by the analysis of the various omes and reactions. All of these conditions have in common factors their interactions, aiming at identifying the molecular inter- that include exposure to a wide range of poorly defined actome underlying any particular status of health and dis- environmental agents, a genetic predisposition, an abnor- ease. These novel approaches are fully applicable to IBD and mal microbial environment and an aberrant immune re- allow us to achieve the ultimate goal of developing and ap- sponse. These four key factors, their combinations and © 2014 S. Karger AG, Basel Claudio Fiocchi, MD 0257–2753/14/0327–0096$39.50/0 Department of Pathobiology, Lerner Research Institute The Cleveland Clinic E-Mail [email protected] Cleveland, Ohio 44195 (USA) www.karger.com/ddi E-Mail fiocchc @ ccf.org Downloaded by: C.H.U. de Vigo 198.143.45.65 - 4/7/2016 12:11:31 PM their interactions can be both similar and different in each type of inflammatory or autoimmune disease, and these similarities and differences are involved in the emergence of any particular disease as well as its fate. The environ- ment, the genetic makeup, the gut microbiota and the mu- Exposome Genome cosal immune response are the currently accepted compo- Color version available online nents of IBD pathogenesis [1] , and this is likely to be cor- IBD rect. Each one of them is recognized to be extremely complex given the fact that the environment around us is made of countless agents, the genes of several hundred Microbiome Immunome variants or mutations, the gut microbiota of trillions of microorganisms and the immune response of dozens of different cell types producing hundreds of biologically ac- tive molecules. Given this complexity, the word ‘compo- nent’, as applied in component of a system, should be re- Fig. 1. The currently accepted four basic components of IBD placed by the word ‘ome’, a Greek-derived suffix that re- pathogenesis represented as overlapping omes: the exposome (en- fers to a totality of some sort. Thus, based on this more vironmental factors), the genome (genetic makeup), the microbi- fitting definition, the four components or ‘omes’ involved ome (gut microbiota) and the immunome (the immune system). in IBD should be respectively called ‘exposome’, ‘genome’, ‘microbiome’ and ‘immunome’ ( fig. 1 ). such as the one by Renz et al. [2] , which envisions more Omes and IBD Pathogenesis than 2 dozen components (omes) and almost as many steps (interactions). Facing this daunting and seemingly One key question related to the above pathogenic qua- overwhelming complexity, it becomes obvious that under- drumvirate is whether all four omes are equally important standing the mechanisms underlying complex conditions in IBD pathogenesis or whether some are more determin- like IBD requires totally new and far more comprehensive ing than others. At the moment there is not enough infor- approaches. This need is exemplarily argued by Fischer [3] : mation to answer this question, but the exposome may ‘To understand complex biological systems it is not enough play a more dominant role given the fact that the genome to characterize the individual molecules in the system. It is cannot have significantly changed in less than a century also necessary to obtain an understanding of the interac- (the period of time when CD and UC appeared), the rec- tions among molecules, particularly in complex diseases. ognition that the gut microbiome is actually part of and With recent technological advances the focus is shifting modulated by the exposome (through diet and xenobiot- toward interpreting data generated by omics technologies, ics), and the assumption that the immunome is nothing that allow to investigate how regulatory processes are dis- more than the consequent effector arm of the intestinal rupted and cause disease.’ In support of this statement is inflammatory response. What is probably correct, how- the comparison between a man-made complex machine, ever, is that no single ome by itself is capable of triggering like a supersonic aircraft, whose advanced performance IBD, and a functional interaction and integration of the depends on innumerous and highly integrated electronic exposome, genome, microbiome and immunome is the circuits, with nature-made but equally if not even more sine qua non condition to develop CD or UC. This forms complex liver cells, which also depend on innumerous and the basis for the concept of an ‘IBD integrome’, and with highly integrated biological circuits [3] . it the need to use ‘omics’ (to be defined later in this review) Another justification for an omics approach to IBD (or as the innovative and unavoidable way to look at IBD. any other complex disorder for the same reason) is the Until recently the traditional paradigm used to explain often forgotten but omnipresent extreme variability of complex diseases included 1 genotype leading to 1 pheno- biological behaviors in humans. Each human being is type and 1 disease, implying 3 components (or 3 omes) and unique and no two alike reactions will ever occur in re- 2 steps (or 2 interactions). With increasing appreciation of sponse to the same identical challenge even in identical biological diversity and complexity in the last couple of de- twins. Let’s take, for example, the response to a tiny and cades, far more intricate paradigms have been proposed, localized proinflammatory stimulus. In a recent study, IBD Omics Dig Dis 2014;32(suppl 1):96–102 97 DOI: 10.1159/000367836 Downloaded by: C.H.U. de Vigo 198.143.45.65 - 4/7/2016 12:11:31 PM blisters were induced by the injection of an irritant in the skin of healthy subjects, who were then given aspirin to limit inflammation [4] . By measuring the variation in the number of inflammatory cells in the blisters, the subjects could be clearly separated into responders and nonre- sponders, with a reduction or lack of reduction of the in- Exposome Genome Color version available online flammatory infiltrates, respectively [4] . With this seem- ingly naive but very informative experiment, it becomes clear that a dichotomy exists in regard to the duration and severity of an acute inflammatory response arising from differentially expressed proresolution pathways. When this notion is applied to far more complicated inflamma- tory processes, such as the one ongoing in the bowel of CD and UC patients, and in a far richer microenviron- ment such as the gut, it is easy to understand why the study of a single ome, no matter in how much depth, can- Microbiome Immunome not provide an answer to the totality of the events result- ing from the interaction with all other pathogenically rel- evant omes. Thus, in light of this evidence two conclu- sions can be reached: (1) IBD is complicated because biology is complicated, and (2) how can we expect to un- derstand or even cure IBD by studying and modulating Fig. 2. The four basic omes of IBD pathogenesis, i.e. the exposome, one single ome at a time, as we currently do? the genome, the microbiome and the immunome, form an IBD integrome, in which each ome interacts with the others through a series of multiple reciprocal positive and negative interactions.