title: The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats.
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.
authors.affiliation: Division of Liver and Biliopancreatic Disorders, University Hospitals Leuven, KU Leuven - University of Leuven, Leuven, Belgium. Electronic address: len.verbeke@med.kuleuven.be.
authors.forename: Len
authors.initials: L
authors.lastname: Verbeke
authors.affiliation: 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.
authors.forename: Ricard
authors.initials: R
authors.lastname: Farre
authors.affiliation: Experimental Laboratory Immunology, KU Leuven - University of Leuven, Leuven, Belgium; Department of Life Sciences, Thomas More Kempen, Geel, Belgium.
authors.forename: Bert
authors.initials: B
authors.lastname: Verbinnen
authors.affiliation: Department of Molecular and Vascular Biology, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Kris
authors.initials: K
authors.lastname: Covens
authors.affiliation: Translational Research Center for Gastrointestinal Disorders, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Tim
authors.initials: T
authors.lastname: Vanuytsel
authors.affiliation: Laboratory of Clinical Bacteriology and Mycology, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Verhaegen
authors.affiliation: Departments of Morphology and Molecular Pathology, Translational Cell and Tissue Research, University Hospitals Leuven, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Mina
authors.initials: M
authors.lastname: Komuta
authors.affiliation: Departments of Morphology and Molecular Pathology, Translational Cell and Tissue Research, University Hospitals Leuven, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Tania
authors.initials: T
authors.lastname: Roskams
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, University Hospitals Leuven, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Sagnik
authors.initials: S
authors.lastname: Chatterjee
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, University Hospitals Leuven, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Annaert
authors.affiliation: Division of Liver and Biliopancreatic Disorders, University Hospitals Leuven, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Vander Elst
authors.affiliation: Division of Liver and Biliopancreatic Disorders, University Hospitals Leuven, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Petra
authors.initials: P
authors.lastname: Windmolders
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Jonel
authors.initials: J
authors.lastname: Trebicka
authors.affiliation: Division of Liver and Biliopancreatic Disorders, University Hospitals Leuven, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Frederik
authors.initials: F
authors.lastname: Nevens
authors.affiliation: Division of Liver and Biliopancreatic Disorders, University Hospitals Leuven, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Laleman
mesh_terms: D000818:Animals; D018988:Bacterial Translocation / Q000187:drug effects*; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D002779:Cholestasis / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D004926:Escherichia coli / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D007082:Ileum / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002635:Chenodeoxycholic Acid; D016207:Cytokines; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C464660:obeticholic acid