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

量化支链氨基酸与其他膳食和微生物营养素相关的肠道代谢

• 批准号: 10614000
• 负责人: Ian Andrew Williamson
• 金额: $ 9万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2023-10-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10614000
• 关键词: Adipose tissue; Affect; Amino Acids; Animal Model; Animals; Antibiotics; Automobile Driving; Bolus Infusion; Branched-Chain Amino Acids; Cardiometabolic Disease; Cell Line; Cells; Communities; Complex; Consumption; Diabetes Mellitus; Diet; Dietary Proteins; Disease; Distant; Engineering; Ensure; Enteral; Enzymes; Equilibrium; Evaluation; Family; Fasting; Food Interactions; Future; Gastroenterology; Genes; Germ-Free; Gluconeogenesis; Glucose; Glutamates; Glutamine; Goals; Homeostasis; Human; Immunosorbent Techniques; Ingestion; Insulin Resistance; Intestinal Secretions; Intestines; Intuition; Knowledge; Laboratories; Link; Liver; Mammals; Measures; Medicine; Mentors; Mentorship; Metabolic; Metabolic Clearance Rate; Metabolic Diseases; Metabolism; Microbe; Microbiology; Modeling; Monitor; Mus; Muscle; Nitrogen; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Nutrient availability; Obesity; Oral; Organoids; Patients; Peptides; Pharmacologic Substance; Physiology; Pilot Projects; Play; Preparation; Probiotics; Production; Propionates; Proteins; Publications; Research; Resistance; Role; Schools; Scientist; Signal Transduction; Sucrose; Technical Expertise; Testing; Therapeutic; Tissues; Trace Elements Nutrition; Training; Transgenic Animals; Translations; Weight Gain; Work; absorption; amino acid metabolism; career; defined contribution; detection of nutrient; diabetic patient; diet-induced obesity; dietary; experience; glucose metabolism; gut microbiota; host-microbe interactions; incretin hormone; interest; liver metabolism; meetings; member; metabolomics; microbial; microbial products; microbiome; microbiota; muscle metabolism; novel therapeutics; nutrient absorption; nutrient metabolism; nutrition; obese patients; obesity treatment; organic acid; oxidation; peptide hormone; programs; response; screening; skills; stable isotope; summer research; synergism; therapeutic target; therapy development; tool; undergraduate research experience; undergraduate student

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.

项目总结/摘要 研究：改变肠促胰岛素分泌和肠促胰岛素生成的药物是有前途的新的 肥胖症和糖尿病的治疗，但其作用机制知之甚少，限制了其 应用程序.必需支链氨基酸（BCAAs）及其代谢产物的循环池升高 代谢物始终与肥胖和糖尿病相关，研究主要集中在肝脏， 不考虑肠道氨基酸代谢。循环支链氨基酸 在哺乳动物中，必须来源于饮食或居住在管腔中的微生物群， BCAA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，向肠道提供显著的能量，减少肠道细胞对葡萄糖的氧化， 尚不清楚BCAA是否会引起类似的代谢变化。肠道也代谢微生物产生的营养物质 如丙酸盐在禁食和进食状态下用于能量和代谢产物的产生。在隔离状态下，微生物产生的 已知营养素和支链氨基酸刺激肽肠促胰岛素激素的分泌， 细胞排列在管腔中，协调全身新陈代谢，为营养负荷做准备。肠促胰岛素反应 和肠道葡萄糖代谢降低，但机制驱动肥胖和糖尿病患者 对失调的了解很少。微生物和膳食营养素之间的协同作用可能有助于 肠促胰岛素失调和/或改变肠代谢影响循环代谢物库。直接测量 饮食和循环中支链氨基酸的代谢将量化肠道代谢的贡献， 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物质和蔗糖的含量将显示肠道代谢是否有助于BCAA的升高 以及与代谢疾病相关的代谢物库。 候选人/培训：长期而言，我计划追求独立的研究生涯，管理跨学科的 实验室开发益生菌和/或药物，其改变肠营养处理以治疗代谢性疾病， 疾病为了实现这一目标，我组建了一个研究目标和一个指导团队，为我提供 基础知识和培训对我的进步至关重要。白色博士是一位代谢生理学家， 许多关于BCAA在其他组织中代谢的高调出版物，将平衡更多的微生物学驱动， 约翰·罗尔斯博士提供的指导。我们已经详细介绍了我将通过他们的培训获得的技术技能， 正式的课程和详细的社区会议，我将参加，以建立必要的技能过渡到 独立一个更大的委员会，包括杜克代谢生理学研究所的主任， 微生物组中心和医学系胃肠病学科主任将 监督我的技术和专业进展，以确保提供足够的支持。