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

The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats

Len Verbeke  1 , Ricard Farre  2 , Bert Verbinnen  3 , Kris Covens  4 , Tim Vanuytsel  5 , Jan Verhaegen  6 , Mina Komuta  7 , Tania Roskams  7 , Sagnik Chatterjee  8 , Pieter Annaert  8 , Ingrid Vander Elst  9 , Petra Windmolders  9 , Jonel Trebicka  10 , Frederik Nevens  9 , Wim Laleman  9
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Free article

The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats

Len Verbeke et al. Am J Pathol. 2015 Feb.
Free article

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.

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