Gastroenterology

Gastroenterology

Volume 134, Issue 2, February 2008, Pages 577-594
Gastroenterology

Reviews in Basic and Clinical Gastroenterology
Microbial Influences in Inflammatory Bowel Diseases

https://doi.org/10.1053/j.gastro.2007.11.059Get rights and content

The predominantly anaerobic microbiota of the distal ileum and colon contain an extraordinarily complex variety of metabolically active bacteria and fungi that intimately interact with the host’s epithelial cells and mucosal immune system. Crohn’s disease, ulcerative colitis, and pouchitis are the result of continuous microbial antigenic stimulation of pathogenic immune responses as a consequence of host genetic defects in mucosal barrier function, innate bacterial killing, or immunoregulation. Altered microbial composition and function in inflammatory bowel diseases result in increased immune stimulation, epithelial dysfunction, or enhanced mucosal permeability. Although traditional pathogens probably are not responsible for these disorders, increased virulence of commensal bacterial species, particularly Escherichia coli, enhance their mucosal attachment, invasion, and intracellular persistence, thereby stimulating pathogenic immune responses. Host genetic polymorphisms most likely interact with functional bacterial changes to stimulate aggressive immune responses that lead to chronic tissue injury. Identification of these host and microbial alterations in individual patients should lead to selective targeted interventions that correct underlying abnormalities and induce sustained and predictable therapeutic responses.

Section snippets

Composition and Metabolic Activity of Commensal Enteric Bacteria

The incredibly complex microbiota of the distal ileum and colon provide an abundant source of potentially detrimental organisms, ligands, and antigens that can activate pathogenic innate and adaptive immune responses, respectively, and metabolic products that affect epithelial and immune functions. These bacteria and their biologically active products are intimately associated with the intestinal mucosa and induce physiologic and pathophysiologically important immune responses. Molecular

Physiologic Microbial/Host Interactions

In normal hosts, commensal bacteria activate a sequential program of homeostatic responses by epithelial cells, macrophages, dendritic cells (DC), T lymphocytes, and B cells/plasma cells that permit coexistence with potentially toxic microbial products.2, 12 Homeostatic mechanisms depend on down-regulating bacterial receptors, inducing intracellular and secreted molecules that terminate innate and adaptive immune responses, and stimulating protective molecules that mediate mucosal barrier

Clinical Evidence

An important role for microbial agents in the pathogenesis of Crohn’s disease and pouchitis is suggested by clinical, experimental, and therapeutic studies, but less convincing evidence is available for ulcerative colitis (Table 1). Crohn’s disease and ulcerative colitis preferentially occur in the colon and distal ileum, which contain the highest intestinal bacterial concentrations. Moreover, the composition and function of the microbiota in Crohn’s disease, ulcerative colitis, and pouchitis

Theories of Pathogenesis

Four broad mechanisms have been proposed to drive pathogenic immunologic responses to luminal microbial antigens (Table 3,Figure 3). These mechanisms increase exposure of bacterial antigens to mucosal T cells or alter host immune responses to commensal bacteria.

Microbial Complications of IBD

Commensal enteric bacteria contribute to local and systemic complications in IBD patients, superinfection with intestinal pathogens cause disease flares, and opportunistic pathogens are increasingly important with widespread immunosuppressive therapy in IBD. Secondary bacterial invasion of mucosal ulcers perpetuates inflammation in Crohn’s disease and causes common septic local complications such as abscesses and fistulae and frequent but severe systemic complications such as hepatic abscesses,

Therapeutic Manipulation of Enteric Bacteria

The use of antibiotics, probiotics, and prebiotics to treat ulcerative colitis, Crohn’s disease, and pouchitis has been extensively reviewed99, 100, 195, 196, 197, 198, 199 and is beyond the scope of this review. Manipulating the abnormal enteric microbiota to decrease the more pathogenic species and enhancing the concentration and metabolic activity of the beneficial species has tremendous potential for therapeutic benefit. However, this rational, physiologic, and nontoxic approach has not yet

Conclusions and Future Directions

The distal ileum and colon are colonized with an extremely complex microbiota that are metabolically active. Alterations in the composition and metabolic profile of commensal bacteria in IBD are very rapidly being defined by molecular techniques. Commensal enteric bacteria and possibly fungi provide the constant antigenic stimulus that drives pathogenic adaptive immune responses in genetically susceptible individuals. A variety of genetic defects in either mucosal barrier function or innate

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    Supported by National Institutes of Health grants (RO1 DK40249, RO1 DK53347, P30 DK34987, P40 RR018603) and the Crohn’s and Colitis Foundation of America.

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