# Role of a common leptin receptor polymorphism in regulating neutrophil heterogeneity after C. difficile infection > **NIH VA I01** · CINCINNATI VA MEDICAL CENTER RESEARCH · 2022 · — ## Abstract Clostridium difficile is the leading nosocomial infection in the U.S and a major concern for VA acute and long- term care facilities. The current therapies for C. difficile infection (CDI) target C. difficile bacterium with antibiotics. But this can leads to killing of commensal bacteria and thus reduce colonization resistance to C. difficile which can in turn promote recurrent CDI. Thus, microbiota sparing approaches for CDI therapy are urgently needed. Magnitude of host neutrophilia is a key regulator of disease outcomes after CDI. We have previously reported a key role for leptin-leptin receptor (LEPR) axis in regulating CDI-induced neutrophilia: our studies revealed that a SNP in LEPR (Q223R), which is present in up to 50% of humans, regulates neutrophil numbers in both mice and patients with CDI. Homozygosity for the mutant LEPR allele (RR genotype) was associated with increased neutrophil counts along with significant tissue damage and higher mortality during acute CDI, but earlier resolution of tissue neutrophilia and clinical disease. Since heterogenous neutrophil populations that contribute to both tissue damage and tissue are critical in regulating infectious disease outcomes, we postulate that different neutrophil types develop in response to C. difficile and contribute to tissue damage and repair. We now have compelling preliminary data that reveals distinct neutrophil populations in bone marrow and colonic tissue of C. difficile infected mice. We have defined these populations based on intra-cellular granules (side scatter on FACS) and 2 integrin (CD11b) expression. In RR mice, an increase in the number of tissue neutrophils (total as well as the activated population, SSChiCD11bhi cells) during acute phase of CDI correlated strongly with severe tissue damage and clinical disease. Subsequently, decline in tissue neutrophils (both total and activated population) was associated with less severe intestinal pathology and earlier recovery from clinical disease in these mice. Further, commensal gut microbiota play an important role in the generation of different neutrophil populations and their mobilization from bone marrow compartment of mice. Our central hypothesis is that LEPR Q to R change is associated with alterations in the gut microbiome that influence the effect of neutrophils on tissue responses to C. difficile in a STAT3-dependent manner. We now propose to comprehensively define the evolution of neutrophil populations during the course of CDI and understand the mechanisms by which LEPR SNP and gut microbiota associated with the SNP regulate formation of distinct neutrophils after CDI. We will answer the following main questions: 1) What are the functional and phenotypic characteristics of neutrophils formed during acute and resolution phase of CDI in both patients and mice with the QQ and RR genotype? 2) How do these neutrophils induce colonic tissue damage and regulate CDI pathogenesis? 3) What is the role of specific gu... ## Key facts - **NIH application ID:** 10476347 - **Project number:** 5I01BX004630-04 - **Recipient organization:** CINCINNATI VA MEDICAL CENTER RESEARCH - **Principal Investigator:** Rajat Madan - **Activity code:** I01 (R01, R21, SBIR, etc.) - **Funding institute:** VA - **Fiscal year:** 2022 - **Award amount:** — - **Award type:** 5 - **Project period:** 2019-07-01 → 2024-06-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10476347 ## Citation > US National Institutes of Health, RePORTER application 10476347, Role of a common leptin receptor polymorphism in regulating neutrophil heterogeneity after C. difficile infection (5I01BX004630-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10476347. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*