Enteroendocrine cells (EECs) are gut epithelial cells that respond to intestinal contents by secreting hormones, including the incretins glucagon-like peptide 1 (GLP-1) and gastric inhibitory protein (GIP), which regulate multiple physiological processes. Hormone release is controlled through metabolite-sensing proteins. Low expression, interspecies differences, and the existence of multiple EEC subtypes have posed challenges to the study of these sensors. We describe differentiation of stomach EECs to complement existing intestinal organoid protocols. CD200 emerged as a pan-EEC surface marker, allowing deep transcriptomic profiling from primary human tissue along the stomach-intestinal tract. We generated loss-of-function mutations in 22 receptors and subjected organoids to ligand-induced secretion experiments. We delineate the role of individual human EEC sensors in the secretion of hormones, including GLP-1. These represent potential pharmacological targets to influence appetite, bowel movement, insulin sensitivity, and mucosal immunity.

Beumer J, Geurts MH, Geurts V, Andersson-Rolf A, Akkerman N, Völlmy F, Krueger D, Busslinger GA, Martínez-Silgado A, Boot C, Yousef Yengej FA, Puschhof J, Van de Wetering WJ, Knoops K, López-Iglesias C, Peters PJ, Vivié JA, Mooijman D, van Es JH, Clevers H. Description and functional validation of human enteroendocrine cell sensors. Science. 2024 Oct 18;386(6719):341-348. doi: 10.1126/science.adl1460. Epub 2024 Oct 17. PMID: 39418382.