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Type: Artigo
Title: Insights Into The Pathogenesis Of Ulcerative Colitis From A Murine Model Of Stasis-induced Dysbiosis, Colonic Metaplasia, And Genetic Susceptibility
Author: Ward
Marc A.; Pierre
Joseph F.; Leal
Raquel F.; Huang
Yong; Shogan
Benjamin; Dalal
Sushila R.; Weber
Christopher R.; Leone
Vanessa A.; Musch
Mark W.; An
Gary C.; Rao
Mrinalini C.; Rubin
David T.; Raffals
Laura E.; Antonopoulos
Dionysios A.; Sogin
Mitch L.; Hyman
Neil H.; Alverdy
John C.; Chang
Eugene B.
Abstract: Gut dysbiosis, host genetics, and environmental triggers are implicated as causative factors in inflanunatory bowel disease (IBD), yet mechanistic insights are lacking. Longitudinal analysis of ulcerative colitis (UC) patients following total colectomy with ileal anal anastomosis (IPAA) where >50% develop pouchitis offers a unique setting to examine cause vs. effect. To recapitulate human IPAA, we employed a mouse model of surgically created blind self-filling (SFL) and self-emptying (SEL) ileal loops using wild-type (WT), IL-10 knockout (KO) (ft-10), TLR4 KO (T4), and IL-10/T4 double KC) mice. After 5 wk, loop histology, host gene/protein expression, and bacterial 16s rRNA profiles were examined. SFL exhibit fecal stasis due to directional motility oriented toward the loop end, whereas SE!, remain empty. In WI mice, SFL, but not SEL, develop pouchlike microbial communities without accompanying active inflammation. However, in genetically susceptible IL-10-deficient mice, SFL, but not SEL, exhibit severe inflammation and mucosal transcriptomes resembling human pouchitis. The inflammation associated with IL-10 required TLR4, as animals lacking both pathways displayed little disease. Furthermore, germ-free IL-10 mice conventionalized with SFL, but not SEL, microbiota populations develop severe colitis. These data support essential roles of stasis induced, colon-like microbiota, TLR4-mediated colonic metaplasia, and genetic susceptibility in the development of pouchitis and possibly UC. However, these factors by themselves are not sufficient. Similarities between this model and htunan UC/pouchitis provide opportunities for gaining insights into the mechanistic basis of IBD) and for identification of targets for novel preventative and therapeutic interventions.
Subject: Pouchitis
Inlammatory Bowel Disease
Ulcerative Colitis
Editor: Amer Physiological Soc
Rights: fechado
Identifier DOI: 10.1152/ajpgi.00017.2016
Date Issue: 2016
Appears in Collections:Unicamp - Artigos e Outros Documentos

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