Farnesoid X Receptor Activation Attenuates Intestinal Ischemia Reperfusion Injury in Rats

Abstract

IntroductionThe 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 MethodsIn 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).ResultsIt 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.ConclusionPretreatment 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.

MicroRNA‐29b‐3p reduces intestinal ischaemia/reperfusion injury via targeting of TNF receptor‐associated factor 3

“…II/R damage caused by bowel infarction, strangulation, severe hypotension, and shock is a frequent and clinically devastating condition with high morbidity and mortality. II/R can cause intestinal mucosal injury and ultimately lead to bacterial translocation, sepsis, multiple organ failure, and eventually death (Ceulemans et al, ; Goldsmith et al, ; Mallick, Yang, Winslet, & Seifalian, ). As mentioned above, apoptosis and inflammation are important mechanisms associated with II/R injury.…”

The farnesoid X receptor agonist obeticholic acid upregulates biliary excretion of asymmetric dimethylarginine via MATE-1 during hepatic ischemia/reperfusion injury

“…Results obtained in a rat model of intestinal I/R injury have recently demonstrated that pretreatment with OCA improves survival, preserves mucosal integrity, inhibits bacterial translocation and reduces pro-inflammatory cytokine release [ 58 ]. Our study provides novel insights into the effects of OCA by showing its capacity to increase MATE-1 expression.…”

Involvement of intestinal hypoperfusion related with Indoleamine 2,3-peroxidase activation and 5-HT metabolism abnormality in intestinal dysfunction after acute myocardial infarction

“…In ammatory pathological changes and IDO activation after AMI Mesenteric hypoperfusion could cause the damage of the intestinal vascular endothelial, the increase of intestinal epithelial permeability, and the gather of in ammatory mediators, as IFN-α,TFN-α,IL-1 [25][26][27]. Besides, as one of in ammatory cells, IDO could also signi cantly increased in a state of in ammation or infection [28].…”