The long-term survival of enteroendocrine cells depends on their subtype and is linked to peripheral sensory innervation.

Enteroendocrine cells (EECs) are sensory epithelial cells that sense the gut luminal environment and convey sensory information to the brain via the visceral afferent pathway. Although EECs are a part of gut epithelial cells, which generally undergo rapid turnover, some EECs have been reported to be long-lived. EECs consist of multiple subtypes, each of which displays distinct hormone production and distribution patterns. It remains unknown whether a long lifespan is a characteristic shared by all EEC subtypes. To address this issue, we conducted genetic pulse labeling of three EEC subtypes expressing serotonin (5-HT), peptide YY (PYY), and gastric inhibitory polypeptide (GIP) in mice and tracked their survival. In the proximal small intestine, all labeled GIP+ EECs disappeared completely within 5 days, whereas some PYY+ EECs survived for more than 7 days. In the proximal colon, some labeled 5-HT+ EECs lived for more than 28 days, whereas no PYY+ cells survived beyond 14 days. These long-lived 5-HT+ EECs were almost exclusively found in the upper half of the crypt in the mucosal fold, where visceral sensory fibers were enriched. This study reveals subtype- and region-dependent survival of EECs and suggests that EEC-nerve communication may underlie the long lifespan of certain EECs.