The FXR Agonist Obeticholic Acid Prevents Gut Barrier Dysfunction and Bacterial Translocation in Cholestatic Rats

Am J Pathol. 2015 Feb;185(2):409-19. doi: 10.1016/j.ajpath.2014.10.009. Epub 2015 Jan 12.

Abstract

Bacterial translocation (BTL) drives pathogenesis and complications of cirrhosis. Farnesoid X-activated receptor (FXR) is a key transcription regulator in hepatic and intestinal bile metabolism. We studied potential intestinal FXR dysfunction in a rat model of cholestatic liver injury and evaluated effects of obeticholic acid (INT-747), an FXR agonist, on gut permeability, inflammation, and BTL. Rats were gavaged with INT-747 or vehicle during 10 days after bile-duct ligation and then were assessed for changes in gut permeability, BTL, and tight-junction protein expression, immune cell recruitment, and cytokine expression in ileum, mesenteric lymph nodes, and spleen. Auxiliary in vitro BTL-mimicking experiments were performed with Transwell supports. Vehicle-treated bile duct-ligated rats exhibited decreased FXR pathway expression in both jejunum and ileum, in association with increased gut permeability through increased claudin-2 expression and related to local and systemic recruitment of natural killer cells resulting in increased interferon-γ expression and BTL. After INT-747 treatment, natural killer cells and interferon-γ expression markedly decreased, in association with normalized permeability selectively in ileum (up-regulated claudin-1 and occludin) and a significant reduction in BTL. In vitro, interferon-γ induced increased Escherichia coli translocation, which remained unaffected by INT-747. In experimental cholestasis, FXR agonism improved ileal barrier function by attenuating intestinal inflammation, leading to reduced BTL and thus demonstrating a crucial protective role for FXR in the gut-liver axis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Translocation / drug effects*
  • Chenodeoxycholic Acid / analogs & derivatives*
  • Chenodeoxycholic Acid / pharmacology
  • Cholestasis / metabolism
  • Cholestasis / microbiology*
  • Cholestasis / pathology
  • Cytokines / biosynthesis
  • Escherichia coli / physiology*
  • Gene Expression Regulation / drug effects
  • Ileum / metabolism
  • Ileum / microbiology*
  • Ileum / pathology
  • Male
  • Rats
  • Rats, Wistar
  • Receptors, Cytoplasmic and Nuclear / agonists*

Substances

  • Cytokines
  • Receptors, Cytoplasmic and Nuclear
  • obeticholic acid
  • farnesoid X-activated receptor
  • Chenodeoxycholic Acid