Gut Bacteria in Health and Disease Eamonn M
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Gut Bacteria in Health and Disease Eamonn M. M. Quigley, MD, FRCP, FACP, FACG, FRCPI Dr Quigley is chief of the Division of Abstract: A new era in medical science has dawned with the real- Gastroenterology and Hepatology at ization of the critical role of the “forgotten organ,” the gut micro- Houston Methodist Hospital in Houston, biota, in health and disease. Central to this beneficial interaction Texas. between the microbiota and host is the manner in which bacteria Address correspondence to: and most likely other microorganisms contained within the gut Dr Eamonn M. M. Quigley communicate with the host’s immune system and participate in Division of Gastroenterology and a variety of metabolic processes of mutual benefit to the host Hepatology and the microbe. The advent of high-throughput methodologies Houston Methodist Hospital and the elaboration of sophisticated analytic systems have facili- 6550 Fannin Street tated the detailed description of the composition of the microbial Houston, TX 77030; Tel: 713-441-0853; constituents of the human gut, as never before, and are now Fax: 713-790-3089; enabling comparisons to be made between health and various E-mail: [email protected] disease states. Although the latter approach is still in its infancy, some important insights have already been gained about how the microbiota might influence a number of disease processes both within and distant from the gut. These discoveries also lay the groundwork for the development of therapeutic strategies that might modify the microbiota (eg, through the use of probiot- ics). Although this area holds much promise, more high-quality trials of probiotics, prebiotics, and other microbiota-modifying approaches in digestive disorders are needed, as well as labora- tory investigations of their mechanisms of action. ue largely to rapidly evolving advances in analytic tech- niques in microbiology, molecular biology, and bioinfor- matics, the true diversity of microorganisms that inhabit Dthe gastrointestinal tract of humans (collectively referred to as the human gut microbiota) is being revealed and its contributions to homeostasis in health and to the pathogenesis of disease appreciated (Table 1). As a consequence, the study of gut ecology has emerged as one of the most active and exciting fields in biology and medicine. It Keywords is in this context that maneuvers to alter or modify the microbiota, Gut flora, microbiota, probiotic, gut bacteria, either through dietary modifications or by the administration of microbial metabolism, mucosal immunology antibiotics, probiotics, or prebiotics, must now be viewed. 560 Gastroenterology & Hepatology Volume 9, Issue 9 September 2013 GUT BACTERIA IN HEALTH AND DISEASE Table 1. Important Homeostatic Functions of the Gut there is accumulating evidence from a number of sources Microbiota that disruption of the microbiota in early infancy may be a critical determinant of disease expression in later life. 1. Metabolic role • Salvages calories It follows that interventions directed at the microbiota • Produces short-chain fatty acids later in life may, quite literally, be too late and potentially • Produces arginine and glutamine doomed to failure. • Synthesizes vitamin K and folic acid Following infancy, the composition of the intestinal • Participates in drug metabolism (eg, activates microflora remains relatively constant until later life. 5-aminosalicylic acid from sulfasalazine) Although it has been claimed that the composition of each 2. Deconjugation of bile acids individual’s flora is so distinctive that it could be used as 3. Prevention of colonization by pathogens an alternative to fingerprinting, more recently, 3 differ- 4. Immunologic effects ent enterotypes have been described in the adult human • Stimulates immunoglobulin A production microbiome.10 These distinct enterotypes are dominated • Promotes anti-inflammatory cytokines and down- by Prevotella, Ruminococcus, and Bacteroides, respectively, regulates proinflammatory cytokines • Induces regulatory T cells and their appearance seems to be independent of sex, age, nationality, and body mass index. The microbiota is thought to remain stable until old age when changes are seen, possibly related to alterations in digestive physiology The Normal Gut Microbiota: and diet.11-13 Indeed, Claesson and colleagues were able to An Essential Factor in Health identify clear correlations in elderly individuals, not only between the composition of the gut microbiota and diet, Basic Definitions and Development of the Microbiota but also in relation to health status.14 The term microbiota is to be preferred to the older term flora, as the latter fails to account for the many nonbacte- Regulation of the Microbiota rial elements (eg, archea, viruses, and fungi) that are now Because of the normal motility of the intestine (peristalsis known to be normal inhabitants of the gut. Given the and the migrating motor complex) and the antimicrobial relatively greater understanding that currently exists of the effects of gastric acid, bile, and pancreatic and intestinal role of bacteria, in comparison with the other constituents secretions, the stomach and proximal small intestine, of the microbiota in health and disease, gut bacteria will be although certainly not sterile, contain relatively small the primary focus of this review. Within the human gastro- numbers of bacteria in healthy subjects.15 Interestingly, intestinal microbiota exists a complex ecosystem of approx- commensal organisms with probiotic properties have imately 300 to 500 bacterial species, comprising nearly recently been isolated from the human stomach.16 The 2 million genes (the microbiome).1 Indeed, the number of microbiology of the terminal ileum represents a transition bacteria within the gut is approximately 10 times that of all zone between the jejunum, containing predominantly aer- of the cells in the human body, and the collective bacterial obic species, and the dense population of anaerobes found genome is vastly greater than the human genome. in the colon. Bacterial colony counts may be as high as At birth, the entire intestinal tract is sterile; the 109 colony-forming units (CFU)/mL in the terminal infant’s gut is first colonized by maternal and envi- ileum immediately proximal to the ileocecal valve, with a ronmental bacteria during birth and continues to be predominance of gram-negative organisms and anaerobes. populated through feeding and other contacts.2 Factors On crossing into the colon, the bacterial concentration known to influence colonization include gestational age, and variety of the enteric flora change dramatically. Con- mode of delivery (vaginal birth vs assisted delivery), diet centrations of 1012 CFU/mL or greater may be found and (breast milk vs formula), level of sanitation, and exposure are comprised mainly of anaerobes such as Bacteroides, to antibiotics.3,4 The intestinal microbiota of newborns is Porphyromonas, Bifidobacterium, Lactobacillus, and Clos- characterized by low diversity and a relative dominance tridium, with anaerobic bacteria outnumbering aerobic of the phyla Proteobacteria and Actinobacteria; thereafter, bacteria by a factor of 100 to 1000:1. The predominance the microbiota becomes more diverse with the emergence of anaerobes in the colon reflects the fact that oxygen con- of the dominance of Firmicutes and Bacteroidetes, which centrations in the colon are very low; the flora has simply characterizes the adult microbiota.5-7 By the end of the first adapted to survive in this hostile environment. year of life, the microbial profile is distinct for each infant; At any given level of the gut, the composition of the by the age of 2.5 years, the microbiota fully resembles the flora also demonstrates variation along its diameter, with microbiota of an adult in terms of composition.8,9 This certain bacteria tending to be adherent to the mucosal period of maturation of the microbiota may be critical; surface, while others predominate in the lumen. It stands Gastroenterology & Hepatology Volume 9, Issue 9 September 2013 561 QUIGLEY to reason that bacterial species residing at the mucosal only are virtually all components of the gut-associated surface or within the mucus layer are those most likely to and systemic immune systems affected in these animals, participate in interactions with the host immune system, but the development of the epithelium, vasculature, neu- whereas those that populate the lumen may be more rel- romuscular apparatus, and gut endocrine system also is evant to metabolic interactions with food or the products impaired. The subtleties of the interactions between the of digestion. It is now evident that different bacterial pop- microbiota and the host are exemplified by studies that ulations may inhabit these distinct domains. Their relative demonstrate the ability of a polysaccharide elaborated by contributions to health and disease have been explored to the bacterium Bacteroides fragilis to correct T-cell deficien- a limited extent, though, because of the relative inacces- cies and Th1/Th2 imbalances and direct the development sibility of the juxtamucosal populations in the colon and, of lymphoid organs in the germ-free animal.24 Intestinal especially, in the small intestine. However, most studies of dendritic cells appear to play a central role in these critical the human gut microbiota have been based on analyses of immunologic interactions.24,25 fecal samples, therefore representing a major limitation. How does the gut immune system differentiate