Reviews in Basic and Clinical GastroenterologyMicrobial Influences in Inflammatory Bowel Diseases
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.