Role of Leptin-Mediated Colonic Inflammation in Defense against Clostridium difficileColitis

ABSTRACTThe role of leptin in the mucosal immune response to Clostridium difficilecolitis, a leading cause of nosocomial infection, was studied in humans and in a murine model. Previously, a mutation in the receptor for leptin (LEPR) was shown to be associated with susceptibility to infectious colitis and liver abscess due to Entamoeba histolyticaas well as to bacterial peritonitis. Here we discovered that European Americans homozygous for the same LEPRQ223R mutation (rs1137101), known to result in decreased STAT3 signaling, were at increased risk of C. difficileinfection (odds ratio, 3.03; P= 0.015). The mechanism of increased susceptibility was studied in a murine model. Mice lacking a functional leptin receptor (db/db) had decreased clearance of C. difficilefrom the gut lumen and diminished inflammation. Mutation of tyrosine 1138 in the intracellular domain of LepRb that mediates signaling through the STAT3/SOCS3 pathway also resulted in decreased mucosal chemokine and cell recruitment. Collectively, these data support a protective mucosal immune function for leptin in C. difficilecolitis partially mediated by a leptin-STAT3 inflammatory pathway that is defective in the LEPRQ223R mutation. Identification of the role of leptin in protection from C. difficileoffers the potential for host-directed therapy and demonstrates a connection between metabolism and immunity.