The role of bacteria in the pathogenesis of inflammatory bowel disease

Abstract

Crohn's disease (CD) and ulcerative colitis (UC) have features that suggest bacterial involvement, and all genetic models of inflammatory bowel disease (IBD) require the presence of commensal bacteria. CD is associated with innate immune response genes such as NOD2/CARD15 and the autophagy genes ATG16L1 and IRGM. However, IBD responds to immunosuppression, suggesting that any bacteria involved are not acting as conventional pathogens. Molecular techniques are rapidly advancing our knowledge of the gut microbiota. In CD there is reduced diversity, and notably a reduction in the probiotic Faecalibacterium prausnitzii, the presence of which in the terminal ileum is associated with a reduced risk of recurrence following surgery. There is also a consistent increase in mucosa-associated Escherichia coli with an "adherent and invasive" phenotype, which allows them to replicate inside macrophages and induce granulomas. Speculation that CD could be caused by the Mycobacterium avium subspecies paratuberculosis (MAP) continues. The response to antitumor necrosis factor treatments suggests that, if relevant at all, MAP is not acting as a conventional pathogen. However, there is increased colonization by MAP in CD, and there is evidence that it could have an indirect effect mediated by the suppression of macrophage function. UC relapse is frequently associated with infection by pathogens, but there is less evidence for involvement of a specific bacterial species. Poor barrier integrity followed by an inflammatory reaction to bacterial components, with chronicity maintained by an autoimmune process, seems a plausible pathogenic model. Bacterial theories of pathogenesis are now becoming testable by targeted therapeutic interventions.

Keywords: Bacteria; Crohn; Escherichia coli; Inflammatory bowel disease; Ulcerative colitis.

Fig. 1

Bacteria-epithelia interaction (reproduced with permission from Knight P, et al. Br Med Bull 2008;88:95-113.126). It is likely that the portal of entry of E. coli commonly isolated from inflammatory bowel disease patients is through specialized microfold "M" cells that exist within the follicle-associated epithelium (FAE). Both the absence of overlying mucus (there are no goblet cells in the FAE) and the diminished glycocalyx present on M cells facilitates interaction with the luminal contents, and thus antigen sampling. E. coli are also shown replicating within macrophages. Dendritic cells participate, possibly by direct sampling of bacteria from the lumen, but also by receipt of bacteria from M cells. Not to scale: the mucus layer, at >100µm, is considerably thicker than the glycocalyx, at <1µm.

Fig. 2

Pathogenesis of inflammatory bowel disease: the evolving model.

Fig. 3

A model for the pathogenesis of Crohn's disease in which mucosal invasion by bacteria, perhaps particularly E. coli, occurs as a result of impairments in the mucosal barrier and/or the innate immune system. ◂ denote possible therapeutic targets.

Fig. 4

A model for bacterial involvement in pathogenesis of ulcerative colitis (Adapted with permission from Rhodes JM. Gut 2007;56:610-612.133).