The secondary bile acids, ursodeoxycholic acid and lithocholic acid, protect against intestinal inflammation by inhibition of epithelial apoptosis.

Natalia K Lajczak‐Mcginley,Ciara M Fallon,Caitriona Curley,Paul A Mccarron,Jessica Smyth,Emanule Porru,Murtaza M Tambuwala,Aldo Roda,Stephen J Keely

doi:10.14814/phy2.14456

Abstract

Increased epithelial permeability is a key feature of IBD pathogenesis and it has been proposed that agents which promote barrier function may be of therapeutic benefit. We have previously reported the secondary bile acid, ursodeoxycholic acid (UDCA), to be protective in a mouse model of colonic inflammation and that its bacterial metabolism is required for its beneficial effects. The current study aimed to compare the effects of UDCA, LCA, and a non‐metabolizable analog of UDCA, 6‐methyl‐UDCA (6‐MUDCA), on colonic barrier function and mucosal inflammation in a mouse model of colonic inflammation. Bile acids were administered daily to C57Bl6 mice by intraperitoneal injection. Colonic inflammation, induced by addition of DSS (2.5%) to the drinking water, was measured as disease activity index (DAI) and histological score. Epithelial permeability and apoptosis were assessed by measuring FITC‐dextran uptake and caspase‐3 cleavage, respectively. Cecal bile acids were measured by HPLC‐MS/MS. UDCA and LCA, but not 6‐MUDCA, were protective against DSS‐induced increases in epithelial permeability and colonic inflammation. Furthermore, UDCA and LCA inhibited colonic epithelial caspase‐3 cleavage both in DSS‐treated mice and in an in vitro model of cytokine‐induced epithelial injury. HPLC‐MS/MS analysis revealed UDCA administration to increase colonic LCA levels, whereas LCA administration did not alter UDCA levels. UDCA, and its primary metabolite, LCA, protect against intestinal inflammation in vivo, at least in part, by inhibition of epithelial apoptosis and promotion of barrier function. These data suggest that clinical trials of UDCA in IBD patients are warranted.

Highlights

Inflammatory bowel diseases, comprised mainly of ulcerative colitis, microscopic colitis, and Crohn's disease, are chronic and recurring disorders of the intestinal tract that are characterized by inflammation of the intestinal wall
We found that administration of the primary colonic metabolite of ursodeoxycholic acid (UDCA), lithocholic acid (LCA), was even more potent than its parent compound in protecting mice from DSS-induced colonic inflammation
The observations that abnormalities in colonic barrier function exist in disease-free first-degree relatives of IBD patients suggest that it may be a fundamental factor in disease onset (Soderholm et al, 1999)

Summary

| INTRODUCTION

Inflammatory bowel diseases, comprised mainly of ulcerative colitis, microscopic colitis, and Crohn's disease, are chronic and recurring disorders of the intestinal tract that are characterized by inflammation of the intestinal wall. Current treatments for IBD make use of a range of anti-inflammatory drugs, including aminosalicylates, glucocorticoids, immunosuppressants, and biologics, with these drugs primarily targeting the mucosal immune system to reduce the inflammatory cell influx and dampen the production of cytokines, chemokines, and pro-inflammatory chemical mediators (Seyedian, Nokhostin, & Malamir, 2019) While these drugs can be effective in inducing or maintaining remission in patients, their clinical utility is often limited by lack of efficacy, development of drug-resistance, or the occurrence of serious side effects and new therapeutic options are still required. We set out to build on our previous work by directly comparing the effects of UDCA and LCA in the DSS model of colonic inflammation and to investigate whether these bile acids exert their beneficial actions by directly targeting cytokine-induced epithelial apoptosis and barrier function

| MATERIALS AND METHODS

| RESULTS

Findings

| DISCUSSION