Enteroendocrine cell lineages that differentially control feeding and gut motility

SUMMARY Enteroendocrine cells are specialized sensory cells of the gut-brain axis that are sparsely distributed along the intestinal epithelium. The functions of enteroendocrine cells have classically been inferred by the gut hormones they release. However, individual enteroendocrine cells typically produce multiple, sometimes apparently opposing, gut hormones in combination, and some gut hormones are also produced elsewhere in the body. Here, we developed approaches involving intersectional genetics to enable selective access to enteroendocrine cells in vivo . We constructed Villin1-p2a-FlpO knock-in mice to restrict reporter expression to intestinal epithelium and through combined use of Cre and Flp alleles, effectively targeted major transcriptome-defined enteroendocrine cell lineages that produce serotonin, glucagon-like peptide 1, cholecystokinin, somatostatin, or glucose insulinotropic peptide. Chemogenetic activation of different enteroendocrine cell types variably impacted feeding behavior, nausea-associated behaviors (conditioned flavor avoidance), and gut motility. Defining the physiological roles of different enteroendocrine cell types provides an essential framework for understanding sensory biology of the intestine.