A Neural Circuit for Gut Microbial Patterns to Regulate Satiety

Abstract

Gut microbes and their host need to eat, but microbes rely on their host to control nutrient intake. Thus, microbes might use their metabolites and molecular patterns to influence the appetite of their host, including the quantity and timing of food intake. But the specific receptors, cells, transmitters, and circuits used by the host to sense and respond to the luminal stimuli of microbial patterns in real time remain unknown. In the small intestine, nutrients elicit fast sensory cues from epithelial neuropod cells that guide appetitive choice. Here, we found that in the mouse colon, microbial flagellin activates toll-like receptor 5 (TLR5) expressed on neuropod cells to reduce food intake. Mice lacking TLR5 in neuropod cells become hyperphagic and overweight. The microbial signal does not act directly on a nerve; instead, it triggers the release of peptide YY by epithelial neuropod cells, which acts on the Y2 receptor expressed in vagal nodose neurons innervating the colon. This feeding behavior change is independent of the common innate immune adaptor MyD88 or metabolic inflammation. Our results reveal a novel sensory modality, distinct from inflammatory responses, that enables an animal host to adjust its appetitive behavior by detecting patterns from its resident microbes in the colon.