Single cell RNA sequencing of human tissue along the stomach-intestinal tract

Enteroendocrine cells (EECs) are gut epithelial cells that respond to
intestinal contents by secreting hormones, including incretins GLP-1 and
GIP, which regulate multiple physiological processes. Hormone release is
controlled through metabolite-sensing proteins. Low expression,
interspecies differences, and 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 hormone
secretion, including GLP-1. These represent potential pharmacological
targets to influence appetite, bowel movement, insulin sensitivity and
mucosal immunity.