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Previously, a mutation in the receptor for leptin (<jats:italic>LEPR<\/jats:italic>) was shown to be associated with susceptibility to infectious colitis and liver abscess due to<jats:named-content content-type=\"genus-species\">Entamoeba histolytica<\/jats:named-content>as well as to bacterial peritonitis. Here we discovered that European Americans homozygous for the same<jats:italic>LEPR<\/jats:italic>Q223R mutation (rs1137101), known to result in decreased STAT3 signaling, were at increased risk of<jats:named-content content-type=\"genus-species\">C. difficile<\/jats:named-content>infection (odds ratio, 3.03;<jats:italic>P<\/jats:italic>= 0.015). The mechanism of increased susceptibility was studied in a murine model. Mice lacking a functional leptin receptor (<jats:italic>db\/db<\/jats:italic>) had decreased clearance of<jats:named-content content-type=\"genus-species\">C. difficile<\/jats:named-content>from 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<jats:named-content content-type=\"genus-species\">C. difficile<\/jats:named-content>colitis partially mediated by a leptin-STAT3 inflammatory pathway that is defective in the<jats:italic>LEPR<\/jats:italic>Q223R mutation. Identification of the role of leptin in protection from<jats:named-content content-type=\"genus-species\">C. difficile<\/jats:named-content>offers the potential for host-directed therapy and demonstrates a connection between metabolism and immunity.<\/jats:p>","DOI":"10.1128\/iai.00972-13","type":"journal-article","created":{"date-parts":[[2013,10,29]],"date-time":"2013-10-29T03:20:30Z","timestamp":1383016830000},"page":"341-349","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":47,"title":["Role of Leptin-Mediated Colonic Inflammation in Defense against Clostridium difficile Colitis"],"prefix":"10.1128","volume":"82","author":[{"given":"Rajat","family":"Madan","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, Virginia, 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