Microbial Maps: Exploring the Role of Spatially-Localized RELMβ Expression in Shaping the Biogeography of the Mouse Gut Microbiome

Abstract

The mammalian gut microbiome is composed of trillions of bacteria that play essential roles in host metabolic functions and immune responses. Changes in the composition of the microbiome have been implicated in diseases including colitis, metabolic disorders, and cancer. The intestinal tract in which the microbes reside is a regionalized structure with distinct cell types lining the intestinal epithelium that produce and secrete antimicrobial proteins (AMPs). The bactericidal activity of these secreted AMPs, together with a mucus layer, form a barrier that protects the host epithelium from bacterial invasion, thus maintaining host-microbiome homeostasis. Prior studies have shown that distinct bacterial species inhabit different regions of the intestine, but whether AMPs have a role in driving bacterial localization patterns is not clearly established. In this work, I build on results acquired from spatial transcriptomics analysis that show that AMPs exhibit differential expression along the length of the large intestine. One such AMP is RELMβ, which is expressed in the large intestine and targets Gram-negative bacteria. Here, I find that localized RELMβ expression is necessary for the spatial separation of bacteria from the host epithelium in the proximal large intestine and that bacterial localization patterns are disrupted in the absence of RELMβ using wild-type and knockout mouse models. These findings suggest that microbial localization is driven by differential host AMP expression and provide novel insight into the spatial regulation of host-microbiome interactions, which has implications for our understanding of intestinal inflammation and disease.