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.

Pathogenesis of Crohn’s disease: Bug or no bug

“…Studies have demonstrated that not only is MAP a possible source for the ASCA mannan epitope, but also that MAP release a mannosecontaining glycoconjugate that impairs the in vitro ability of monocyte-derived macrophages to kill phagocytosed E. coli. Therefore, as Friswell suggests, MAP might be acting via an indirect pathogenic effect, which would explain its role in pathogenesis and yet not be greatly exacerbated by anti-TNF treatment [44,53] . ASCA may develop a long time before the diagnosis of CD is established.…”

“…This raises the possibility that a combination of bacterial components, including FimH, linked to GP2, may be presented as a foreign antigen and thus lead to development of anti-GP2 antibodies, in a way analogous to the development of anti-tissue transglutaminase antibodies in celiac disease. As Friswell et al [44] highlight in their review of the role of bacteria in the pathogenesis of IBD, blockade of bacterial entry via M cells represents an important target for therapies. In a very recent paper [45] , certain isolates of E. coli have been shown to be related both with colorectal cancer and IBD.…”

“…Metaanalyses have shown reactivity in CD patients' sera, to MAP p35 and p36 recombinant antigens. However, it should be noted that MAP p35 and p36 are similar to that of Mycobacterium avium, subspecies avium [MAA], so a specific reaction to MAP rather than MAA cannot be certain [44] . An increased presence of MAPreactive T cells has also been found in CD patients but not in controls [52] .…”

“…Mycobacterium avium subspecies paratuberculosis is an obligate pathogenic organism that causes Johne's disease [44] in ruminants and other animals such as primates and rabbits. Johne's disease is a chronic wasting diarrheal disease [18] with clinical and histological conditions that are highly evocative of CD [46] .…”

Ulcerative Colitis and Microorganisms

“…The main theories that try to explain Ulcerative Colitis aetiopathogenesis by means of an infectious agent can be summarized as follows: -Dysbiosis hypothesis which implies that an imbalance between beneficial versus detrimental resident intestinal bacterial species may incite chronic inflammatory responses (Friswell et al 2010). -Persistent infection hypothesis which proposes that Ulcerative Colitis may arise as a result of persistent infection with enteric pathogens (Khan et al, 2011).…”