Project Summary/Abstract Research: Pharmaceuticals modifying intestinal incretin secretion and gluconeogenesis are promising new therapies for obesity and diabetes mellitus, but their mechanisms of action are poorly understood limiting their application. Elevated circulating pools of the essential branched-chain amino acids (BCAAs) and their metabolites are consistently associated with obesity and diabetes with research primarily focused on liver and muscle metabolism of dietary protein without considering intestine amino acid metabolism. Circulating BCAAs in mammals must either originate from the diet or the microbiota residing in the lumen that upregulates its expression of BCAA enzymes in obese and insulin-resistant animal models. The amino acid glutamine provides significant energy to the intestine in fasted and fed states, reducing glucose oxidation by intestine cells but it is not known if BCAAs drive similar metabolic changes. The intestine also metabolizes microbe-produced nutrients like propionate in fasted and fed states for energy and metabolite production. In isolation, microbe-produced nutrients and BCAAs are known to stimulate the secretion of peptide incretin hormones from nutrient sensing cells lining the lumen that coordinate whole body metabolism in preparation for a nutrient load. Incretin response and enteric glucose metabolism are reduced in obese and diabetic patients but the mechanisms driving dysregulation are poorly understood. Synergy between microbe-produced and dietary nutrients could contribute to incretin dysregulation and/or alter enteric metabolic effecting circulating metabolite pools. Directly measuring the metabolism of dietary and circulating BCAAs will quantify the contribution of intestine metabolism to circulating BCAA and metabolite pools. Determining if intestine BCAA metabolism interacts with the metabolism of microbiota-produced nutrients and sucrose will show if intestine metabolism contributes to the elevated BCAA and metabolite pools associated with metabolic disease. Candidate/Training: Long term, I plan to pursue an independent research career managing an interdisciplinary laboratory developing probiotics and/or pharmaceuticals that change intestine nutrient handling to treat metabolic disease. In pursuit of this goal, I have assembled research aims and a mentoring team to provide me with the foundational knowledge and training essential to my progress. Dr. White, an expert metabolic physiologist with many high-profile publications on BCAA metabolism in other tissues, will balance the more microbiology-driven mentorship provided by Dr. John Rawls. We have detailed the technical skills I will gain through their training or formal courses and detailed the community meetings I will attend to build the necessary skills to transition to independence. A larger committee including the directors of Duke’s Metabolic Physiology Institute and Microbiome Center as well as the Chief of the Division of Gastroenterology in the Department of Medicine will monitor my technical and professional progress to ensure adequate support is provided.

Project Narrative Interest in intestine metabolism grew rapidly when the gluconeogenesis and fructolysis functions of the intestine were identified. Recently developed metabolic therapeutics target these intestine metabolic functions and the locally produced regulatory peptide hormones, but our understanding of their mechanisms of action is incomplete limiting treatment development and application. I aim to measure intestine metabolism of an obesity-associated metabolite family, branched-chain amino acids, regarding other dietary and microbial nutrients to complete our understanding of the involvement of intestine metabolism in whole-body metabolite profiles.