TY - JOUR
T1 - Farnesoid X Receptor Activation Attenuates Intestinal Ischemia Reperfusion Injury in Rats
AU - Ceulemans, Laurens J.
AU - Verbeke, Len
AU - Decuypere, Jean-Paul
AU - Farre, Ricard
AU - De Hertogh, Gert
AU - Lenaerts, Kaatje
AU - Jochmans, Ina
AU - Monbaliu, Diethard
AU - Nevens, Frederik
AU - Tack, Jan
AU - Laleman, Wim
AU - Pirenne, Jacques
PY - 2017/1/6
Y1 - 2017/1/6
N2 - 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 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 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-beta, TNF alpha, IFN-gamma 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.
AB - 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 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 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-beta, TNF alpha, IFN-gamma 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.
KW - INFLAMMATORY-BOWEL-DISEASE
KW - EPITHELIAL TIGHT JUNCTIONS
KW - BILE-ACID RECEPTOR
KW - OBETICHOLIC ACID
KW - NUCLEAR RECEPTOR
KW - NONALCOHOLIC STEATOHEPATITIS
KW - FXR
KW - BARRIER
KW - AUTOPHAGY
KW - AGONIST
U2 - 10.1371/journal.pone.0169331
DO - 10.1371/journal.pone.0169331
M3 - Article
C2 - 28060943
SN - 1932-6203
VL - 12
JO - PLOS ONE
JF - PLOS ONE
IS - 1
M1 - e0169331
ER -