Shifts in the composition of gut bacterial populations can alter host metabolism and may contribute to the pathogenesis of metabolic disorders, including
obesity. Mice deficient in
leptin action are obese with altered microbiota and increased susceptibility to certain intestinal pathogens. Because
antimicrobial peptides (AMPs) secreted by Paneth cells represent a major mechanism by which the host influences the gut microbiome, we examined the
mRNA expression of gut AMPs, several of which were decreased in
leptin receptor (LepR)-deficient db/db mice, suggesting a potential role for
AMP modulation of microbiota composition. To address the extent to which the alterations in gut microbiota and
AMP mRNA expression in db/db mice result from increased food intake vs other defects in
leptin action, we examined the effects of pair feeding and gut epithelial LepRb ablation on
AMP mRNA expression and microbiota composition. We found that the phylum-level changes in fecal microbial content and
AMP gene expression persist in pair-fed db/db mice, suggesting that these differences do not stem from
hyperphagia alone. In addition, despite recent evidence to support a role for intestinal epithelial LepRb signaling in pathogen susceptibility, ablation of LepRb from the intestinal epithelium fails to alter
body weight, composition of the microbiota, or
AMP expression, suggesting a role for LepRb elsewhere for this regulation. Indeed, gut LepRb cells are not epithelial but rather constitute a previously uncharacterized population of perivascular cells within the intestinal submucosa. Overall, our data reveal a role for LepRb signaling extrinsic to the intestinal epithelium and independent of food intake in the control of the gut microbiome.