A substrate for durable gut-brain signaling

Duke University, Durham NC

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Humans prefer foods to which they have been exposed early in life. This has significant implications for obesity as early exposure to foods with excess sugar can lead to unhealthy food choices later in life. However, the mechanism by which early food exposure leads to long-term changes in food preferences is unclear. Recently, it has been established that specialized sensory cells in the gut epithelium called neuropod cells respond to sugar within the small intestine. Further, neuropod cells are essential for driving choices for sucrose over artificial sweetener. Therefore, it stands to reason that neuropod cells could be involved in long-term food preferences. However, enteroendocrine cells, a class of cells in the gut epithelium that includes neuropod cells, are believed to turn over rapidly with some studies suggesting a lifespan as short as three-to-five days. Therefore, it is unclear if the longevity of neuropod cells supports a role in long-term food preferences. Preliminary data included in this proposal finds a population of neuropod cells, called long-lived neuropod cells, that can live up to six months—a quarter of the life of the animal. Further, these preliminary data show that long-lived neuropods have more connections with sensory neurons than their less mature counterparts. Because in other sensory systems like olfaction, active receptors survive, and it has been established that neuropod cells reliably respond to sugar in the small intestine, this proposal hypothesizes that response to sugar leads to increased connections with neurons that facilitate survival. The first aim of this proposal will test this hypothesis using a 2D gut organoid model to evaluate the effect of supplemental sugar and the presence of neurons on neuropod cell activity and survival. The second aim of this proposal will focus on the function of long-lived neuropods with regards to sugar preferences. Using a combination of targeted ablation and optogenetic inhibition, this proposal aims to show that long-lived neuropods are necessary for the establishment and maintenance of long-term sugar preferences. Overall, this proposal will seek to characterize a long-lived gut-brain pathway and define its role in terms of long-term gustatory behavior. This has significant implications for obesity, but since chronic gastrointestinal disorders such as the Disorders of Gut-Brain Interaction (DGBI), which include irritable bowel syndrome and chronic constipation, are also believed to act via a gut-brain mechanism, defining a functional long-lived gut-brain circuit is essential for the study of these diseases as well. In addition to making a significant contribution to the study of gut-brain interactions, this fellowship includes critical technical and knowledge-based training in sensory biology for Dr. Zachary Lorsch. Combined with training in leadership, mentorship, and communications provided by sponsor Dr. Diego Bohórquez and co-sponsor Dr. Rodger Liddle, this fellowship will allow Dr. Lorsch to fuse his background in molecular neuroscience with his clinical training in gastroenterology and become a successful physician- scientist researcher at the intersection of neuroscience and gastroenterology.