2. Academic Validation
  3. The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats

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.
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
Affiliations

Affiliations

  • 1 Division of Liver and Biliopancreatic Disorders, University Hospitals Leuven, KU Leuven - University of Leuven, Leuven, Belgium. Electronic address: len.verbeke@med.kuleuven.be.
  • 2 Translational Research Center for Gastrointestinal Disorders, KU Leuven - University of Leuven, Leuven, Belgium; Center for Biomedical Research, Network for Liver and Digestive Diseases (CIBERehd), Instituto de Salud Carlos II, Barcelona, Spain.
  • 3 Experimental Laboratory Immunology, KU Leuven - University of Leuven, Leuven, Belgium; Department of Life Sciences, Thomas More Kempen, Geel, Belgium.
  • 4 Department of Molecular and Vascular Biology, KU Leuven - University of Leuven, Leuven, Belgium.
  • 5 Translational Research Center for Gastrointestinal Disorders, KU Leuven - University of Leuven, Leuven, Belgium.
  • 6 Laboratory of Clinical Bacteriology and Mycology, KU Leuven - University of Leuven, Leuven, Belgium.
  • 7 Departments of Morphology and Molecular Pathology, Translational Cell and Tissue Research, University Hospitals Leuven, KU Leuven - University of Leuven, Leuven, Belgium.
  • 8 Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, University Hospitals Leuven, KU Leuven - University of Leuven, Leuven, Belgium.
  • 9 Division of Liver and Biliopancreatic Disorders, University Hospitals Leuven, KU Leuven - University of Leuven, Leuven, Belgium.
  • 10 Department of Internal Medicine I, University of Bonn, Bonn, Germany.
PMID: 25592258 DOI: 10.1016/j.ajpath.2014.10.009
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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