Quantifying Enteric Metabolism of Branched-chain Amino Acids in Relation to Other Dietary and Microbiota Nutrients

项目概要/摘要 研究：改变肠促胰素分泌和糖异生的药物是有前途的新药物 肥胖和糖尿病的治疗方法，但对其作用机制知之甚少，限制了其作用 应用程序。必需支链氨基酸 (BCAA) 及其相关物质的循环池升高 代谢物始终与肥胖和糖尿病相关，研究主要集中在肝脏和糖尿病上 肌肉代谢膳食蛋白质而不考虑肠道氨基酸代谢。循环支链氨基酸 哺乳动物中的细菌必须来自饮食或内腔中的微生物群，这些微生物群可以上调其 支链氨基酸酶在肥胖和胰岛素抵抗动物模型中的表达。氨基酸谷氨酰胺提供 在禁食和进食状态下，为肠道提供大量能量，减少肠道细胞对葡萄糖的氧化，但它是 尚不清楚支链氨基酸是否会引起类似的代谢变化。肠道还代谢微生物产生的营养物质 就像禁食和进食状态下的丙酸一样，用于产生能量和代谢物。孤立地，微生物产生 已知营养物质和支链氨基酸可通过营养感应刺激肽肠促胰岛素激素的分泌 管腔内的细胞协调全身代谢，为营养负荷做好准备。肠促胰岛素反应 肥胖和糖尿病患者的肠道葡萄糖代谢降低，但驱动机制 人们对调节失调知之甚少。微生物产生的营养物质和膳食营养物质之间的协同作用可能有助于 肠促胰素失调和/或改变肠道代谢影响循环代谢物池。直接测量 膳食和循环支链氨基酸的代谢将量化肠道代谢对 循环支链氨基酸和代谢物池。确定肠道 BCAA 代谢是否与代谢相互作用 微生物群产生的营养素和蔗糖的含量将显示肠道代谢是否导致 BCAA 升高 以及与代谢疾病相关的代谢物池。 候选人/培训：从长远来看，我计划从事管理跨学科的独立研究职业 实验室开发益生菌和/或药物，改变肠道营养处理以治疗代谢 疾病。为了实现这一目标，我制定了研究目标和指导团队，为我提供 对我的进步至关重要的基础知识和培训。怀特博士是一位代谢生理学家专家 许多关于其他组织中支链氨基酸代谢的备受瞩目的出版物，将平衡更多微生物学驱动的 由约翰·罗尔斯博士提供指导。我们详细介绍了我将通过他们的培训或培训获得的技术技能 我将参加正式课程和详细的社区会议，以培养过渡到的必要技能 独立性。一个更大的委员会，包括杜克大学代谢生理学研究所的主任和 微生物组中心以及医学系胃肠科主任将 监控我的技术和专业进展，以确保提供足够的支持。

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.