What is the role of the enteric commensal flora in IBD?

Abstract

Infectious diseases are produced by specific microbial agents that possess the capacity of transmitting the disease to susceptible individuals. An infectious origin of Crohn's disease (CD) or ulcerative colitis (UC) is not supported by such a criterion since direct transmission of these diseases has never been documented. However, there is a substantial body of evidence implicating the commensal enteric bacteria in the pathogenesis of both CD and UC. Luminal bacteria appear to provide the stimulus for immuno-inflammatory responses leading to mucosal injury.1,2 The normal mucosal defense is based mainly on the production of IgA antibodies that are secreted into the gut lumen where they neutralize microbes, thus avoiding mucosal inflammation.2 In IBD, however, mucosal production of IgG antibodies against intestinal bacteria is highly increased, and mucosal defense relies on both IgG-mediated responses within the tissue and hyperactivated lymphocytes in the lamina propria reacting against bacterial antigens.1,–3 These combined events result in inflammation and tissue injury. The altered immune response is not specifically addressed or polarized toward a single group of potential pathogens, but involves a large and undefined number of commensal species belonging to the common enteric flora. Several factors may contribute to the abnormal reactivity of the mucosal immune system against enteric bacteria, and these include genetic susceptibility, a defect in mucosal barrier function, and a microbial imbalance in the gut ecosystem.1 The term “microflora” or “microbiota” refers to the community of living microorganisms assembled in a particular ecological niche of a host individual. Microbial communities act as a single ecosystem and are capable of adapting to radical habitat alterations by altering community physiology and composition. In this way they are able to maintain stability in structure and function over time. The human gut is the natural habitat for a large, diverse, and dynamic population of microorganisms that over millennia have adapted to live on the mucosal surfaces or in the lumen.3 The number of resident bacteria increases along the small bowel, from ≈104 in the jejunum to 107 colony-forming units per gram of luminal content at the ileal end. The large intestine is the most heavily populated organ, where several hundred grams of bacteria are harbored at densities around 1012 colony-forming units per gram of luminal content. Over 50% of bacteria cells that are observed by microscopic examination of fecal specimens cannot be grown in culture. Molecular biological techniques based on the sequence diversity of the bacterial genome are now being used to characterize noncultivable bacteria. Studies on the fecal microbiota have highlighted the diversity of the flora between individuals. Each individual harbors his or her own distinctive pattern of bacterial composition. This pattern appears to be determined at least in part by the host genotype, because similarity in fecal bacterial species is much higher within twins than genetically unrelated couples that share environment and dietary habits. In healthy adults the fecal composition is host-specific and stable over time, but temporal fluctuations due to environmental factors can be detected and may involve up to 20% of the strains. Bacterial composition in the lumen varies from the cecum to the rectum, and fecal samples do not reflect luminal contents at proximal segments. Nevertheless, the community of mucosal-associated bacteria is highly stable from the terminal ileum to the large bowel in a given individual (95% similarity between the different anatomical locations). The interaction between gut bacteria and their host is a symbiotic relationship mutually beneficial for both partners. The host provides a nutrient-rich habitat and the bacteria confer important benefits to the host. Functions of the microbiota include nutrition (fermentation of nondigestible substrates that results in production of short chain fatty acids, absorption of ions, production of amino acids, and vitamins), protection (the barrier effect that prevents invasion by alien microbes), and important trophic effects on the intestinal epithelium and the immune system (development and homeostasis of local and systemic immunity). Animals bred in a germ-free environment show lower densities of lymphoid cells in the gut mucosa and lower levels of serum immunoglobulins. Exposure to commensal microbes rapidly expands the number of mucosal lymphocytes and increases the size of germinal centers in lymphoid follicles. Immunoglobulin-producing cells appear in the lamina propria, and there is a significant increase in serum immunoglobulin levels. Some commensal bacteria seem to play a dominant role in the induction of regulatory T cells in gut lymphoid follicles. Regulatory pathways mediated by regulatory T cells are essential homeostatic mechanisms, through which the host can tolerate the massiv