Insights into the pathogenesis of ulcerative colitis from a murine model of stasis-induced dysbiosis, colonic metaplasia, and genetic susceptibility.

Abstract

Gut dysbiosis, host genetics, and environmental triggers are implicated as causative factors in inflammatory 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) (IL-10), TLR4 KO (T4), and IL-10/T4 double KO 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 SEL remain empty. In WT 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 human UC/pouchitis provide opportunities for gaining insights into the mechanistic basis of IBD and for identification of targets for novel preventative and therapeutic interventions.

• Authors: Marc A Ward, Joseph F Pierre, Raquel F Leal, Yong Huang, Benjamin Shogan, Sushila R Dalal, Christopher R Weber, Vanessa A Leone, Mark W Musch, Gary C An, Mrinalini C Rao, David T Rubin, Laura E Raffals, Dionysios A Antonopoulos, Mitch L Sogin, Neil H Hyman, John C Alverdy, Eugene B Chang
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 310 Issue 11 Pg. G973-88 (06 01 2016) ISSN: 1522-1547 [Electronic] United States
• PMID: 27079612 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 the American Physiological Society.

Chemical References

• IL10 protein, mouse
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• Interleukin-10

Topics

• Animals
• Colitis, Ulcerative (etiology)
• Dysbiosis (complications)
• Female
• Gastrointestinal Motility
• Humans
• Interleukin-10 (genetics, metabolism)
• Intestinal Mucosa (metabolism)
• Intestines (microbiology, pathology, physiopathology)
• Mice
• Mice, Inbred C57BL
• Microbiota
• Toll-Like Receptor 4 (genetics, metabolism)