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Bile Acids Modulate Colonic MAdCAM‐1 Expression in a Murine Model of PSC‐IBD
Author(s) -
Gao Rachel Y.,
Shearn Colin,
Orlicky David,
Battista Kayla,
Alexeev Erica,
Cartwright Ian,
Kostelecky Rachael,
Colgan Sean,
Fennimore Blair
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.06593
Subject(s) - primary sclerosing cholangitis , addressin , ursodeoxycholic acid , inflammatory bowel disease , medicine , colitis , bile acid , cholestasis , proinflammatory cytokine , ulcerative colitis , inflammation , gastroenterology , immunology , disease , integrin , receptor
Background & Objective Primary Sclerosing Cholangitis (PSC) is a progressive cholestatic liver disease of unknown etiology that carries a strong association with inflammatory bowel disease (IBD). PSC‐associated IBD (PSC‐IBD) displays a unique colitis phenotype characterized by right side predominant inflammation and increased risk of colorectal cancer compared to non‐PSC‐IBD. Although the initiation/progression PSC‐IBD remains unclear, some evidence supports an integral role for the gut‐specific mucosal vascular addressin cell adhesion molecule (MAdCAM‐1) in modulating both hepatic and intestinal inflammation. Multidrug resistance protein 2 (Mdr2) knockout mice develop spontaneous cholestatic liver injury and fibrosis mirroring human PSC. To further elucidate disease mechanisms of PSC‐IBD, we combined Mdr2−/− mice with the chemically inducible model of DSS colitis (Mdr2−/−/DSS). We hypothesize that alterations in bile acids promote mucosal inflammation in this murine model of combined cholestasis/colitis. There are currently no good models for PSC‐IBD, so our objective is to develop a murine model mimicking PSC‐IBD for studying the gut‐liver axis and proinflammatory crosstalk.Methods & Results Mice were fed 1.5% DSS for 5 days and recovered for 4 days before being euthanized. Transformed sinusoidal endothelial cells (TSECs) were treated with 5 ng/ml of TNF‐αand/or 100μM of ursodeoxycholic acid (UDCA). UDCA treated mice were fed 0.5% UDCA fortified chow for 2 weeks and throughout the previously described DSS course. In this model, Mdr2−/− mice displayed marked alterations in intestinal bile acid composition and increased susceptibility to DSS colitis based on weight loss, disease activity index, histology, and inflammatory cytokines, etc. Mdr2−/− mice also displayed an upregulation of colonic MAdCAM‐1 expression as compared to C57BL/6 colitis controls. In vitro work utilizing transformed sinusoidal endothelial cells (TSECs) and bEnd.3 cells (brain endothelial cells) revealed that MAdCAM‐1 was potently induced by TNF‐α and that this induction was significantly attenuated by co‐treatment with ursodeoxycholic acid (UDCA). In vivo , DSS‐treated Mdr2−/− mice fed with UCDA fortified chow demonstrated significant attenuation of colitis susceptibility and decreased colonic MAdCAM‐1 expression as compared to standard chow controls. Conclusions These findings suggest a unique interplay between alterations in bile acid homeostasis and intestinal MAdCAM‐1 expression in modulating pro‐inflammatory cross‐talk along the gut‐liver axis and identify intestinal bile acid signaling as a potential therapeutic target for the treatment of PSC‐IBD. Support or Funding Information University of Colorado GI and Liver Innate Immune Program (GALIIP)