Microbiota-sourced purines in gut health and disease

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PROJECT SUMMARY To protect the host and perform their symbiotic role, intestinal epithelial cells secrete large amounts of highly glycosylated mucin to physically distance yet provide bacteria habitat and fuel, while establishing apical junction complexes that regulate nutrient and waste flux. In return, a healthy microbiota functions to provide metabolites the epithelium relies on for function. We recently published that the purine hypoxanthine (Hpx) is a microbiota-derived metabolite that the mucosa depends upon for energy balance, barrier function, and wound healing, suggesting Hpx as a limiting substrate for homeostatic mucosal metabolism and function. In unbiased extensions of that work, we demonstrated that Hpx induces TP53-inducible glycolysis and apoptosis regulator (TIGAR) expression and activates AMP-activated kinase (AMPK) in vitro and in vivo. TIGAR increases metabolite flux through the pentose phosphate pathway while AMPK is a master regulator of metabolism that promotes energy balance. We hypothesize that Hpx fundamentally molds epithelial metabolism through TIGAR and AMPK as mechanisms that support intestinal homeostasis and wound healing. In this, purine depletion and reconstitution by colonization experiments with a developed mutant E. coli enriched in Hpx production will be employed to determine the influence of microbiota-derived Hpx on mucosal energy metabolism, barrier function, and wound healing. The applicant, Dr. Lee, has established a scientific niche in which to build a foundation for independent research in the role of microbiota-derived purines in gut mucosal energy metabolism and function. Dr. Lee and his mentor, Dr. Colgan, assembled an advisory committee to regularly meet as a group with Dr. Lee throughout the duration of the award to provide feedback on the research, critique the research plans, monitor publications, and provide career advice. Drs. Colgan and Lee also identified microbiology and immunology courses to facilitate expansion of Dr. Lee's foundation of knowledge in fundamental intestinal processes, and established tutelage in colonic enteroid harvesting/culturing for study and in histopathological analyses. Dr. Lee will submit his work to present at conferences specific to his research to share his research and network with colleagues and potential collaborators, and get valuable feedback from the scientific community. Dr. Lee's development will benefit from continued participation in the Mucosal Inflammation Program (MIP), a multi- disciplinary, multi-departmental program initiated to study mechanisms of mucosal inflammation and resolution. The MIP fosters a unique lab environment for collaboration between physician scientists, clinicians, and research scientists, and works to establish an environment for young investigators to flourish and develop. The facilities and resources available to and development plan built for Dr. Lee provide an ideal environment and path for his successful transition to independence.