SUMMARY Despite the clear link between sugar overconsumption and metabolic syndrome, how the gut senses and communicates the presence of sugar to the brain remains unknown. Studies have shown that preference for sugars depends not on their sweet taste in the oral cavity, but rather on their entrance into the intestine. Therefore, understanding how the gut communicates information about ingested sugars could open a new path for pharmacotherapeutics for treating metabolic disease. The mechanisms of sensing nutrients in the gut are thought to involve the slower paracrine and endocrine action of peptides released from enteroendocrine cells. In recent years it has become evident that in addition to their canonical paracrine function, enteroendocrine cells also form synapses with nerves in the underlying intestinal and colonic mucosa. These gut epithelial cells that form synapses are known as neuropod cells. Our overall hypothesis is that glutamatergic neuropod cells in the small intestine transduce sugar stimuli to guide sugar preference. This hypothesis builds on recent observations: 1) the duodenal epithelium contains a population of glutamatergic neuropod cells labeled by the vesicular glutamate transporter 1; 2) vagal nerve firing in response to intraduodenal sugar stimuli depends on glutamatergic signaling; and 3) a mouse's preference for sugar over non-caloric sweetener is abolished by silencing a subset of enteroendocrine cells. The objectives in this application are three-fold: 1) to determine how glutamatergic neuropod cells are activated by sugar; 2) to establish the glutamatergic gut-to-vagus nerve signaling pathway activated by sugars; and 3) to determine the role of glutamatergic neuropod signaling on sugar preference. The outcomes of this research could serve as a foundation to design gut-based pharmacotherapies that seek to curb the desire to consume sugar by targeting the receptors and signaling molecules of glutamatergic epithelial cells.