Role of Leptin-Mediated Colonic Inflammation in Defense against Clostridium difficile Colitis

Abstract

fThe 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.

Persistence and Toxin Production by Clostridium difficile within Human Intestinal Organoids Result in Disruption of Epithelial Paracellular Barrier Function

“…The pathogenesis of CDI is multifaceted and involves interactions between the host, the gut microbiota, and C. difficile (22)(23)(24). In order to study the effect of C. difficile colonization on human epithelium, we developed techniques to colonize the HIO lumen with viable vegetative C. difficile.…”

Role of obesity and adipose tissue-derived cytokine leptin during Clostridium difficile infection

“…While the functional consequences of LEPR Q223R polymorphism have not been completely elucidated, our studies have shown that the polymorphism affects downstream STAT3 signaling with the wild type 223Q allele having a more robust STAT3 signal after leptin stimulation as compared to the mutant 223R allele (50), without any affects on the binding kinetics of leptin to it’s receptor (51). Recently, we have shown that the odds of having C. difficile infection are increased in individuals homozygous for the 223R allele as compared to heterozygous or those homozygous for the 223Q allele (OR = 3.03; p = 0.01) (52). …”

“…Mechanistically, both leptin- and leptin receptor-deficient ( ob/ob or db/db respectively) mice were resistant to toxin A-induced ileal fluid secretion (53). The role of leptin signaling during infection (rather than intoxication) with C. difficile had not been studied until our recent work, which demonstrated that leptin signaling leads to increased inflammation and clinical signs of disease acutely after C. difficile infection (52). This heightened response to infection was associated with better control of pathogen burden during acute infection (Day 2, peak disease) as measured by levels of Toxin A/B and C. difficile -specific glutamate dehydrogenase (GDH) in the cecal contents (52).…”

“…The role of leptin signaling during infection (rather than intoxication) with C. difficile had not been studied until our recent work, which demonstrated that leptin signaling leads to increased inflammation and clinical signs of disease acutely after C. difficile infection (52). This heightened response to infection was associated with better control of pathogen burden during acute infection (Day 2, peak disease) as measured by levels of Toxin A/B and C. difficile -specific glutamate dehydrogenase (GDH) in the cecal contents (52). Notably, mice with uncoupled leptin receptor-STAT3 signaling had diminished colonic inflammation, decreased colonic chemokine and immune cell recruitment, and less severe clinical signs of disease (52).…”

Host recognition of Clostridium difficile and the innate immune response

“…Inflammatory signaling by pattern recognition receptors has also been shown to be protective during CDI, as Nod1 -/- , MyD88 -/- and TLR4 -/- mice all experience more severe disease [31-33]. Leptin signaling also appears to be protective, as leptin deficient mice show higher bacterial burdens [44]. The cytokine interleukin-23 (IL-23) stands out as an inducer of pathogenic inflammation during infection [45].…”