Enteric sensory neurons for nutrient detection and gut motility

Summary The enteric nervous system (ENS) orchestrates gastrointestinal reflexes and brain-gut communication via molecularly diverse neurons. Among these, intrinsic primary afferent neurons (IPANs) are essential for detecting luminal nutrients and irritants, yet their molecular identities, sensory properties, and functions remain poorly resolved. Here, we establish a segment-resolved single-cell atlas of the murine ENS, including a comprehensive characterization of the gastric ENS. This resource defines a refined taxonomy of enteric neurons and glia and enabled the development of a genetic toolkit for molecularly defined IPANs. Using chemogenetics and calcium imaging, we discovered that myenteric neurons detect a wide range of nutrients, irritants, and cytokines. Nutrient detection depends on a functional connection between chemosensory epithelial cells and enteric neurons mediated by 5-HT—HTR3 axis. Through optogenetic analysis, we demonstrated segment-specific regulation of gut motility by different IPANs. Our work establishes a genetic and physiological framework for enteric-specific sensory mechanisms.