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.

项目摘要/摘要 研究：修饰肠道增加和糖异生的药物有望新 肥胖症和糖尿病的疗法，但它们的作用机理对限制了他们 应用。基本分支链氨基酸（BCAA）的循环池及其循环池及其 代谢物一直与肥胖和糖尿病有关，主要针对肝脏和 饮食蛋白的肌肉代谢，而无需考虑肠氨基酸代谢。循环BCAA 在哺乳动物中，必须源自饮食或属于腔内的微生物群 BCAA酶在肥胖和胰岛素耐药性动物模型中的表达。氨基酸谷氨酰胺提供 在禁食和饲养状态下肠道的重要能量，减少了肠细胞的葡萄糖氧化，但它是 不知道BCAA是否驱动类似的代谢变化。肠子还代谢微生物生产的营养素 就像在禁食和饲养状态下用于能源和代谢物生产的状态一样。分离，产生了微生物 众所周知，营养和BCAA会刺激辣椒的分泌增加，从营养传感器增加 衬里的细胞，以辅助全身代谢的管腔为营养负荷做准备。泌尿素反应 肥胖和糖尿病患者的肠葡萄糖代谢降低了 失调的理解很少。微生物生产和饮食营养素之间的协同作用可能有助于 增加失调和/或改变的促进代谢作用的循环代谢物池。直接测量 饮食和循环BCAA的代谢将量化肠道代谢对 循环的BCAA和代谢物池。确定肠道BCAA代谢是否与代谢相互作用 生产的微生物群和蔗糖的肠道代谢是否有助于升高的BCAA 与代谢疾病相关的代谢物池。 候选人/培训：长期，我计划从事跨学科的独立研究职业 实验室开发益生菌和/或药物会改变肠道营养的处理以治疗代谢 疾病。为了实现这一目标，我已经组装了研究目标和一个心理团队，为我提供了 基础知识和培训对我的进步至关重要。怀特博士，专家代谢生理学家 许多有关其他组织中BCAA代谢的备受瞩目的出版物将平衡以微生物为导向的 约翰·罗尔斯（John Rawls）博士提供的资术。我们已经详细介绍了通过他们的培训或 正式的课程和详细介绍我将参加的社区会议，以建立过渡到过渡到的必要技能 独立。一个更大的委员会，包括杜克大学代谢生理研究所的董事 微生物组中心以及医学系胃肠病学系长 监视我的技术和专业进步，以确保提供足够的支持。