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Title: The FXR Agonist Obeticholic Acid Prevents Gut Barrier Dysfunction and Bacterial Translocation in Cholestatic Rats
Authors: Verbeke, Len ×
Farré, Ricard
Verbinnen, Bert
Covens, Kris
Vanuytsel, Tim
Verhaegen, Jan
Komuta, Mina
Roskams, Tania
Chatterjee, Sagnik
Annaert, Pieter
Vander Elst, Ingrid
Windmolders, Petra
Trebicka, Jonel
Nevens, Frederik
Laleman, Wim #
Issue Date: Feb-2015
Series Title: American Journal of Pathology vol:185 issue:2 pages:409-419
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.
ISSN: 0002-9440
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Translational Research in GastroIntestinal Disorders
Hepatology
Groep Gezondheid en Welzijn TM K - miscellaneous
Mechanical Engineering Technology TC, Technology Campus Geel
Experimental Laboratory Immunology
Laboratory of Clinical Bacteriology and Mycology
Translational Cell & Tissue Research
Drug Delivery and Disposition
× corresponding author
# (joint) last author

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