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
  • 1. Division of Liver and Biliopancreatic Disorders, University Hospitals Leuven, KU Leuven - University of Leuven, Leuven, Belgium. Electronic address: [email protected].
  • 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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