Publication Date:
2022-05-26
Description:
Author Posting. © The Author(s), 2016. This is the author's version of the work. It is posted here by permission of American Physiological Society for personal use, not for redistribution. The definitive version was published in American
Journal of Physiology-Gastrointestinal and Liver Physiology 310 (2016): G973-G988, doi:10.1152/ajpgi.00017.2016.
Description:
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 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 KO (IL10), and TLR4 KO (T4), and
IL10/T4 double KO mice. After 5 weeks, loop histology, host gene/protein expression, and
bacterial 16s rRNA profiles were examined. SFL exhibit fecal stasis due to directional motility
oriented towards the loop end, whereas SEL remain empty. In wild type mice, SFL, but not SEL,
develop pouch-like 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 IL10-/- 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.
Description:
NIDDK DK42086 (DDRCC), UH3 DK083993, Leona and Harry
Helmsley Trust (SHARE), R37 DK47722, T32 DK07074, F32 DK105728, Gastrointestinal
Research Foundation of Chicago, Peter and Carol Goldman Family Research grant.
Description:
2017-06-01
Keywords:
Pouchitis
;
Inflammatory Bowel Disease
;
Ulcerative Coltiis
;
Dysbiosis
Repository Name:
Woods Hole Open Access Server
Type:
Preprint
Permalink
