The ability to detect and respond appropriately to ingested nutrients is essential for an organism’s survival and to ensure its metabolic demands are met. Nutrient signals from the gut lumen trigger local intestinal reflexes in the enteric nervous system (ENS) to facilitate digestion and absorption1–4, but the precise cellular pathways that are involved in the initial neuronal sensory process remain unclear. The extent to which the ENS is capable of discerning different luminal chemicals is also unknown. Here we use calcium imaging to identify specific enteric pathways that are activated in response to luminal nutrients applied to mouse jejunum. Notably, we show that different nutrients activate neurochemically defined ensembles of myenteric and submucosal neurons. Furthermore, we find that enteric neurons are not directly sensitive to nutrients but detect different luminal chemicals through the epithelium, mainly via a serotonin signalling pathway. Finally, our data reveal a spatial distribution of luminal information along the radial axis of the intestine, whereby some signals that originate from the villus epithelium are transmitted first to the myenteric plexus, and then back to the submucosal plexus, which is closer to the lumen.
