Farnesoid X Receptor Activation Attenuates Intestinal Ischemia Reperfusion Injury in Rats

PLoS One. 2017 Jan 6;12(1):e0169331. doi: 10.1371/journal.pone.0169331. eCollection 2017.

Abstract

Introduction: 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.

Material and 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.

Conclusion: 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.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Autophagy / drug effects
  • Biomarkers
  • Chenodeoxycholic Acid / analogs & derivatives
  • Chenodeoxycholic Acid / pharmacology
  • Disease Models, Animal
  • Endotoxins / metabolism
  • Ileum / blood supply
  • Ileum / drug effects
  • Ileum / metabolism
  • Ileum / pathology
  • Inflammation Mediators / metabolism
  • Intestinal Mucosa / metabolism*
  • Intestines / blood supply*
  • Intestines / drug effects
  • Intestines / pathology
  • Male
  • Permeability
  • Rats
  • Receptors, Cytoplasmic and Nuclear / agonists
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Reperfusion Injury / drug therapy
  • Reperfusion Injury / metabolism*
  • Reperfusion Injury / mortality
  • Reperfusion Injury / pathology
  • Signal Transduction / drug effects

Substances

  • Biomarkers
  • Endotoxins
  • Inflammation Mediators
  • Receptors, Cytoplasmic and Nuclear
  • obeticholic acid
  • farnesoid X-activated receptor
  • Chenodeoxycholic Acid

Grants and funding

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. L J Ceulemans was granted a research fee by the Belgian Federation for Gastroenterology (BWGE), the Flemish Society for Gastroenterology (VVGE) and the Royal Belgian Surgical Society (RBSS). L Verbeke is an aspirant-researcher and was granted a PhD fellowship by the Fund for Scientific Research – Flanders (FWO Vlaanderen). D Monbaliu and F Nevens are senior clinical investigators for the Fund for Scientific Research – Flanders (FWO Vlaanderen). J Tack is supported by a Methusalem grant from the University of Leuven, Belgium. J Pirenne has received grants from Ku Leuven, FWO and unrestricted grants form Roche and Astellas. J Pirenne and D Monbaliu received a CAF chair for Abdominal Transplantation research.