title: Farnesoid X Receptor Activation Attenuates Intestinal Ischemia Reperfusion Injury in Rats.
abstract: BACKGROUND
  The farnesoid X receptor (FXR) is abundantly expressed in the ileum, where it exerts an enteroprotective role as a key regulator of intestinal innate immunity and homeostasis, as shown in pre-clinical models of inflammatory bowel disease. Since intestinal ischemia reperfusion injury (IRI) is characterized by hyperpermeability, bacterial translocation and inflammation, we aimed to investigate, for the first time, if the FXR-agonist obeticholic acid (OCA) could attenuate intestinal ischemia reperfusion injury.
  
  
  METHODS
  In a validated rat model of intestinal IRI (laparotomy + temporary mesenteric artery clamping), 3 conditions were tested (n = 16/group): laparotomy only (sham group); ischemia 60min+ reperfusion 60min + vehicle pretreatment (IR group); ischemia 60min + reperfusion 60min + OCA pretreatment (IR+OCA group). Vehicle or OCA (INT-747, 2*30mg/kg) was administered by gavage 24h and 4h prior to IRI. The following end-points were analyzed: 7-day survival; biomarkers of enterocyte viability (L-lactate, I-FABP); histology (morphologic injury to villi/crypts and villus length); intestinal permeability (Ussing chamber); endotoxin translocation (Lipopolysaccharide assay); cytokines (IL-6, IL-1-β, TNFα, IFN-γ IL-10, IL-13); apoptosis (cleaved caspase-3); and autophagy (LC3, p62).
  
  
  RESULTS
  It was found that intestinal IRI was associated with high mortality (90%); loss of intestinal integrity (structurally and functionally); increased endotoxin translocation and pro-inflammatory cytokine production; and inhibition of autophagy. Conversely, OCA-pretreatment improved 7-day survival up to 50% which was associated with prevention of epithelial injury, preserved intestinal architecture and permeability. Additionally, FXR-agonism led to decreased pro-inflammatory cytokine release and alleviated autophagy inhibition.
  
  
  CONCLUSIONS
  Pretreatment with OCA, an FXR-agonist, improves survival in a rodent model of intestinal IRI, preserves the gut barrier function and suppresses inflammation. These results turn FXR into a promising target for various conditions associated with intestinal ischemia.
authors.affiliation: Abdominal Transplant Surgery, University Hospitals Leuven, & Department of Microbiology and Immunology, KU Leuven, Belgium.
authors.forename: Laurens J
authors.initials: LJ
authors.lastname: Ceulemans
authors.affiliation: Liver and Biliopancreatic Disorders, University Hospitals Leuven, KU Leuven, Belgium.
authors.forename: Len
authors.initials: L
authors.lastname: Verbeke
authors.affiliation: Abdominal Transplant Surgery, University Hospitals Leuven, & Department of Microbiology and Immunology, KU Leuven, Belgium.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Decuypere
authors.affiliation: Gastro-enterology, University Hospitals Leuven, & Translational Research in Gastro-Intestinal Disorders (TARGID), KU Leuven, Belgium.
authors.forename: Ricard
authors.initials: R
authors.lastname: Farré
authors.affiliation: Translational Cell and Tissue Research, University Hospitals Leuven, & Department of Imaging and Pathology, KU Leuven, Belgium.
authors.forename: Gert
authors.initials: G
authors.lastname: De Hertogh
authors.affiliation: Department of Surgery, Maastricht University Medical Centre, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, the Netherlands.
authors.forename: Kaatje
authors.initials: K
authors.lastname: Lenaerts
authors.affiliation: Abdominal Transplant Surgery, University Hospitals Leuven, & Department of Microbiology and Immunology, KU Leuven, Belgium.
authors.forename: Ina
authors.initials: I
authors.lastname: Jochmans
authors.affiliation: Abdominal Transplant Surgery, University Hospitals Leuven, & Department of Microbiology and Immunology, KU Leuven, Belgium.
authors.forename: Diethard
authors.initials: D
authors.lastname: Monbaliu
authors.affiliation: Liver and Biliopancreatic Disorders, University Hospitals Leuven, KU Leuven, Belgium.
authors.forename: Frederik
authors.initials: F
authors.lastname: Nevens
authors.affiliation: Gastro-enterology, University Hospitals Leuven, & Translational Research in Gastro-Intestinal Disorders (TARGID), KU Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Tack
authors.affiliation: Liver and Biliopancreatic Disorders, University Hospitals Leuven, KU Leuven, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Laleman
authors.affiliation: Abdominal Transplant Surgery, University Hospitals Leuven, & Department of Microbiology and Immunology, KU Leuven, Belgium.
authors.forename: Jacques
authors.initials: J
authors.lastname: Pirenne
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D015415:Biomarkers; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D004731:Endotoxins / Q000378:metabolism; D007082:Ileum / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology; D008297:Male; D010539:Permeability; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D015415:Biomarkers; D002635:Chenodeoxycholic Acid; D004731:Endotoxins; D018836:Inflammation Mediators; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C464660:obeticholic acid