title: Role of leptin-mediated colonic inflammation in defense against Clostridium difficile colitis.
abstract: The role of leptin in the mucosal immune response to Clostridium difficile colitis, 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 histolytica as well as to bacterial peritonitis. Here we discovered that European Americans homozygous for the same LEPR Q223R mutation (rs1137101), known to result in decreased STAT3 signaling, were at increased risk of C. difficile infection (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. difficile 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 C. difficile colitis partially mediated by a leptin-STAT3 inflammatory pathway that is defective in the LEPR Q223R mutation. Identification of the role of leptin in protection from C. difficile offers the potential for host-directed therapy and demonstrates a connection between metabolism and immunity.
authors.affiliation: Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Rajat
authors.initials: R
authors.lastname: Madan
authors.forename: Xiaoti
authors.initials: X
authors.lastname: Guo
authors.forename: Caitlin
authors.initials: C
authors.lastname: Naylor
authors.forename: Erica L
authors.initials: EL
authors.lastname: Buonomo
authors.forename: Donald
authors.initials: D
authors.lastname: Mackay
authors.forename: Zannatun
authors.initials: Z
authors.lastname: Noor
authors.forename: Patrick
authors.initials: P
authors.lastname: Concannon
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Scully
authors.forename: Patcharin
authors.initials: P
authors.lastname: Pramoonjago
authors.forename: Glynis L
authors.initials: GL
authors.lastname: Kolling
authors.forename: Cirle A
authors.initials: CA
authors.lastname: Warren
authors.forename: Priya
authors.initials: P
authors.lastname: Duggal
authors.forename: William A
authors.initials: WA
authors.lastname: Petri
mesh_terms: D000818:Animals; D018925:Chemokines / Q000378:metabolism; D016360:Clostridioides difficile / Q000235:genetics / Q000276:immunology; D003015:Clostridium Infections / Q000235:genetics / Q000276:immunology; D003092:Colitis / Q000235:genetics / Q000382:microbiology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease; D007413:Intestinal Mucosa / Q000276:immunology; D007422:Intestines / Q000382:microbiology; D020738:Leptin / Q000276:immunology / Q000502:physiology*; D016015:Logistic Models; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D054411:Receptors, Leptin / Q000172:deficiency / Q000235:genetics*; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D014443:Tyrosine / Q000235:genetics
chemical_list: D018925:Chemokines; D016207:Cytokines; D020738:Leptin; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D014443:Tyrosine