The Importance Of The Enteric Microbiota In Inflammatory Bowel Disease

Considerable evidence implicates the enteric microbiota in the pathogenesis of inflammatory bowel disease (Table 1) (7,8,30,31). Firstly, mucosal inflammation occurs in areas of the gut with highest bacterial numbers. Secondly, surgical diversion of the fecal stream has been associated with clinical improvement in the distal bowel, but relapse is predictable following surgical restoration. Thirdly, putative therapeutic efficacy is seen with the use of antibiotics in colonic disease. Fourthly, immune reactivity to intestinal bacteria is detectable in patients with inflammatory bowel disease suggesting a loss of immune tolerance to components of the microbiota (32,33). Fifthly, there are reports of increased numbers of bacteria within the mucosa of patients with inflammatory bowel disease compared with controls (34,35). The highest bacterial numbers have been seen in CD patients and numbers increase with severity of disease. Finally, the description of the first susceptibility gene for CD, CARD15/NOD2, has provided a basis for explaining the interaction between bacteria and the immune response. CARD15/NOD2 encodes a protein

Table 1 Evidence Implicating the Enteric Microbiota in the Pathogenesis of IBD

The distribution of the lesions is greatest in areas of highest numbers of luminal bacteria Interruption of the fecal stream has been associated with clinical improvement but relapse is predictable following surgical restoration Evidence for loss of immunological tolerance to components of the commensal microbiota Serology and cellular immune reactivity to enteric microbiota that has formed the basis of putative diagnostic tests Efficacy of antibiotics in patients

Description of first susceptibility gene for Crohn's disease (CARD15/NOD2)

Colonization with normal enteric microbiota is required for expression of disease in animal models of colitis irrespective of the underlying defect Attenuation of inflammation in animal models of enterocolitis Efficacy of probiotics in animal models of colitis Effect of probiotics in human studies of IBD

Abbreviation: IBD, inflammatory bowel disease.

that is involved in the recognition of bacterial products and initiates the inflammatory cascade via activation of the transcription factor Nuclear Factor kappaB (NFkB) (36,37).

Compelling evidence for the interactive role of genes, bacteria, and immunity has been derived from experimental animal models of both Crohn's-like and colitis-like disease (38,39). There are now about 30 different spontaneously occurring or genetically engineered (knockout or transgenic) animal models for inflammatory bowel disease (40-42). Colonization with normal enteric microbiota is required for full expression of disease. Thus, the normal microbiota is a common factor driving the inflammatory process irrespective of the genetic underlying predisposition and immunological effector mechanism (43,44). Several different microorganisms have been demonstrated to induce colitis in animal models. These include Enterococcus faecalis, causing colitis in the antiinflammatory interleukin-10 (IL-10) knockout mice, and Bacteroides vulgatus, which induced inflammation in the HLA-B27 rat model (45,46). This evidence has prompted the therapeutic modification of the enteric microbiota in inflammatory bowel disease.

In patients with ulcerative colitis, the construction of an ileal pouch following a colectomy represents a human "model" showing the contribution of genes, bacteria, and immune mechanisms to its pathogenesis. A genetic contribution is consistent with the relative frequency of pouchitis in patients undergoing surgery for colitis compared with those having a pouch created surgically for familial polyposis coli. The contribution of bacteria to the pathogenesis of pouchitis is shown by the efficacy of both antibiotic and probiotic therapy in treating the disease (47). The immune system mediates the tissue damage and pouchitis appears to be a colitis-like process occurring in the colonized ileum.

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