Metabolomic interrogation of gut mechanosensing in Drosophila

Project description Gut epithelium is the principal site in which neural, immune, microbial and dietary factors interact. These multi-system interactions critically regulate whole-body physiology including metabolism, immunity, and neurodegenerative diseases. Gut epithelium is exposed to a myriad of mechanical forces that are generated by gut peristalsis and food passing. These forces include shear stress, stretch, and compression. Despite growing interest in mechanobiology, mechanisms of gut mechanosensing and its effects on physiology and diseases remain largely unexplored. In this project, we explore the impact of gut mechanosensing on metabolism and aging-related dysplasia. The adult Drosophila midgut has emerged as a simple but robust genetic model system for investigation of gut growth and physiology. We have recently begun to elucidate the cellular and molecular mechanisms of gut mechanosensing by showing that shear stress could activate enteroendocrine cells through the transient receptor potential A1 (TrpA1) ion channel. Moreover, disruption of TrpA1-mediated gut mechanosensing could significantly impact intestine stem cell proliferation. In our pilot study, we have made novel and exciting findings that many gut metabolites including lipids are altered in TrpA1 mutants. In this collaborative project, we will synergize our expertise on gut mechanobiolgy and state-of-the-art metabolomic analysis, and combine it with the power of Drosophila genetics, to determine the impact of gut mechanosensing on systemic metabolism in intact tissues. We also propose to define the signaling mechanisms that link gut mechanosensing to aging-related dysplasia. Completion of this project will provide a conceptual advance of how gut mechanosensing could play a role in metabolism and aging. Given that each cell type in the Drosophila gut epithelium has conserved functions with its mammalian counterpart, we further expect that our results could provide some insights on gut mechanobiology in mammals.