title: 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.affiliation: Department of Surgery, University of Chicago, Chicago, Illinois;
authors.forename: Marc A
authors.initials: MA
authors.lastname: Ward
authors.affiliation: Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago, Illinois;
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Pierre
authors.affiliation: Colorectal Surgery Unit, Department of Surgery, University of Campinas, Campinas, Sao Paulo, Brazil;
authors.forename: Raquel F
authors.initials: RF
authors.lastname: Leal
authors.affiliation: Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago, Illinois;
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Surgery, University of Chicago, Chicago, Illinois;
authors.forename: Benjamin
authors.initials: B
authors.lastname: Shogan
authors.affiliation: Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago, Illinois;
authors.forename: Sushila R
authors.initials: SR
authors.lastname: Dalal
authors.affiliation: Department of Pathology, University of Chicago, Chicago, Illinois;
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Weber
authors.affiliation: Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago, Illinois;
authors.forename: Vanessa A
authors.initials: VA
authors.lastname: Leone
authors.affiliation: Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago, Illinois;
authors.forename: Mark W
authors.initials: MW
authors.lastname: Musch
authors.affiliation: Department of Surgery, University of Chicago, Chicago, Illinois;
authors.forename: Gary C
authors.initials: GC
authors.lastname: An
authors.affiliation: Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois;
authors.forename: Mrinalini C
authors.initials: MC
authors.lastname: Rao
authors.affiliation: Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago, Illinois;
authors.forename: David T
authors.initials: DT
authors.lastname: Rubin
authors.affiliation: Department of Medicine, Mayo Clinic, Rochester, Minnesota;
authors.forename: Laura E
authors.initials: LE
authors.lastname: Raffals
authors.affiliation: Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago, Illinois; Biosciences Division, Argonne National Laboratory, Argonne, Illinois; and Institute for Genomics and Systems Biology, University of Chicago, Chicago, Illinois.
authors.forename: Dionysios A
authors.initials: DA
authors.lastname: Antonopoulos
authors.affiliation: Josephine Bay Paul Center, Biosciences Division, Marine Biological Laboratory at Woods Hole, Woods Hole, Massachusetts;
authors.forename: Mitch L
authors.initials: ML
authors.lastname: Sogin
authors.affiliation: Department of Surgery, University of Chicago, Chicago, Illinois;
authors.forename: Neil H
authors.initials: NH
authors.lastname: Hyman
authors.affiliation: Department of Surgery, University of Chicago, Chicago, Illinois;
authors.forename: John C
authors.initials: JC
authors.lastname: Alverdy
authors.affiliation: Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago, Illinois; echang@medicine.bsd.uchicago.edu.
authors.forename: Eugene B
authors.initials: EB
authors.lastname: Chang
mesh_terms: D000818:Animals; D003093:Colitis, Ulcerative / Q000209:etiology*; D064806:Dysbiosis / Q000150:complications*; D005260:Female; D005769:Gastrointestinal Motility; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D064307:Microbiota; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism
chemical_list: C556062:IL10 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016753:Interleukin-10
keywords: dysbiosis; inflammatory bowel disease; pouchitis; ulcerative colitis