A gut sense for nutrients

Interoception relies fundamentally on the ability of visceral organs to detect and communicate rapidly to the brain. A central puzzle in this field is how the gastrointestinal tract drives distinct behavioral preferences for nutritive sugars over non-caloric sweeteners, despite both stimuli activating similar taste receptors. However, how the gut steers such preferences via specific neural coding remains a critical question. We hypothesized that neuropod cells utilize distinct neurotransmission modalities to differentiate between caloric and non-caloric stimuli, thereby signaling specific nutrient value to the vagus nerve. To test this, we investigated duodenal neuropod cells using a combination of receptor profiling, in vitro and in vivo electrophysiology and imaging, and behavioral assays. Our results demonstrate that neuropod cells transduce luminal sweetener using sweet taste receptors and nutritive sugar using sodium-glucose transporters; then release different neurotransmitters on to vagal neurons to drive feeding behavior. Specifically, we found that non-caloric sweeteners stimulated purinergic neurotransmission, whereas caloric sugars stimulated glutamatergic neurotransmission. Behaviorally, mice displayed a robust preference for sugar over sweetener, but silencing neuropod cells, or their glutamatergic signaling, abolished this preference. We conclude that neuropod cells serve as the primary sensory entry point for gut interoception, utilizing a precise neurotransmission code to swiftly discern the identity of nutrient stimuli. This mechanism explains how the gut guides nutritive choices and provides a cellular basis for understanding how interoceptive processing influences metabolic health. Supported by: K01 DK131403-01A1(M.M.K.); DP2 DP2DK147450 (M.M.K.). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.