The Secondary Bile acids, Ursodeoxycholic acid and Lithocholic Acid, Protect Against Intestinal Inflammation by Inhibition of Epithelial Apoptosis

Natalia K. Lajczak-McGinley, Emanule Porru, Ciara M. Fallon, Jessica Smyth, Caitriona Curley, P. A. McCarron, Murtaza M Tambuwala, Aldo Roda, Stephen J. Keely

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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.

Original languageEnglish
Article numbere14456
Number of pages11
JournalPhysiological Reports
Volume8
Issue number12
Early online date19 Jun 2020
DOIs
Publication statusE-pub ahead of print - 19 Jun 2020

Keywords

  • apoptosis
  • bile acid
  • colitis
  • epithelial barrier function

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