Farnesoid X Receptor Activation Attenuates Intestinal Ischemia Reperfusion Injury in Rats

Laurens J. Ceulemans*, Len Verbeke, Jean-Paul Decuypere, Ricard Farre, Gert De Hertogh, Kaatje Lenaerts, Ina Jochmans, Diethard Monbaliu, Frederik Nevens, Jan Tack, Wim Laleman, Jacques Pirenne

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

26 Citations (Web of Science)

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 reper-fusion 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-beta, TNF alpha, IFN-gamma 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.

Original languageEnglish
Article numbere0169331
Number of pages17
JournalPLOS ONE
Volume12
Issue number1
DOIs
Publication statusPublished - 6 Jan 2017

Keywords

  • INFLAMMATORY-BOWEL-DISEASE
  • EPITHELIAL TIGHT JUNCTIONS
  • BILE-ACID RECEPTOR
  • OBETICHOLIC ACID
  • NUCLEAR RECEPTOR
  • NONALCOHOLIC STEATOHEPATITIS
  • FXR
  • BARRIER
  • AUTOPHAGY
  • AGONIST

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