A comprehensive research resource to define mechanisms underlying microbial regulation of host metabolism in pediatric obesity and obesity-targeted therapeutics

一个全面的研究资源，用于定义儿科肥胖和肥胖靶向治疗中宿主代谢的微生物调节机制

• 批准号: 9166349
• 负责人: John F Rawls
• 金额: $ 158.56万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-25 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9166349
• 关键词: Adolescence; Adolescent; Adolescent obesity; Adult; Age; Animal Model; Bacteria; Blood; Body Weight; Branched-Chain Amino Acids; Child; Childhood; Clinical; Communities; Comorbidity; Coronary heart disease; Data; Databases; Development; Diabetes Mellitus; Disease; Economically Deprived Population; Enrollment; Enzymes; Epidemic; Epidemiology; Equilibrium; Etiology; Fatty Acids; Feces; Gene Expression; Genes; Genetic; Germ-Free; Gnotobiotic; Goals; Health; Human; Insulin Resistance; Intervention; Intestines; Knowledge; Lead; Link; Longevity; Mediating; Metabolic; Metabolism; Methods; Microbe; Mission; Molecular; Molecular Profiling; Morbid Obesity; Mus; Muscle; North Carolina; Obesity; Observational Study; Outcome; Outpatients; Pathway Analysis; Patients; Peripheral Blood Mononuclear Cell; Phenocopy; Phenotype; Plant Roots; Plasma; Population; Prevention; Production; Public Health; Regulation; Research; Resources; Risk; Sampling; Specimen; Staging; Taxon; Technology; Testing; Therapeutic; Treatment Efficacy; Treatment outcome; United States National Institutes of Health; Weight Gain; Weight maintenance regimen; Work; Youth; acylcarnitine; bacterial genetics; base; cardiovascular risk factor; cohort; disadvantaged population; effective therapy; fatty acid oxidation; fecal transplantation; genetic analysis; gut microbiota; improved; innovation; insight; insulin sensitivity; intervention program; meetings; metabolic profile; metabolomics; microbial; microbial community; microbiome; microbiota; molecular dynamics; novel; novel strategies; obesity in children; obesity treatment; pandemic disease; research study; response; targeted treatment; tool; trait; weight loss intervention

PROJECT SUMMARY The current pandemic of obesity and insulin resistance across the lifespan presents an immense public health challenge. Human observational studies and fecal transplantation studies in animal models (both largely focused on adults) have found an interconnection among obesity, insulin resistance, and the microbiota. Because epidemiology points to childhood origins for the genesis of obesity, there is a critical need to understand the mechanisms of pediatric obesity and to develop tools for its prediction, prevention, and treatment. Children with severe obesity mimic adult phenotypes in their development of metabolic and cardiovascular risk, and yet are at the earliest stages of disease with fewer and less severe co-morbid conditions. Thus children with obesity present a unique opportunity and an ideal population in which to garner deeper insights into the obesity-associated microbiome. To enable such insights, the objective of this proposal is to establish a comprehensive research resource to define mechanisms underlying microbial regulation of host metabolism in adolescents with obesity (ages 12-18 yrs) before and after weight loss intervention. The proposed research leverages Duke’s unique and well-established intervention program for pediatric obesity and insulin resistance. Our prior studies have applied metabolomic technology to reveal that blood metabolites such as branched chain amino acids (BCAA) are negatively associated with insulin sensitivity following adult weight loss interventions, and we have used gnotobiotic mice to demonstrate their positive association with microbiota-mediated weight gain. Our preliminary studies indicate that BCAA and related metabolites are also associated with insulin resistance and weight gain in adolescents. Our central hypothesis is that human gut bacteria control host weight gain and insulin resistance in adolescents by modifying host metabolism. This hypothesis will be tested in two specific aims: Aim 1. Develop a resource to define associations between intestinal microbiota and a severely obese population of adolescents enrolled in an outpatient weight management intervention program. Aim 2. Define the molecular mechanisms by which human intestinal bacteria regulate metabolic traits linked to pediatric obesity. Completion of this work will provide three key resources for broad use by the scientific community: (1) a clinical sample, microbiota strain, and data repository from a unique pediatric weight management intervention cohort, (2) a comprehensive suite of robust genetic, molecular profiling, and phenotyping technologies that will yield unique insights into the microbial communities that control body weight and responses to obesity intervention, and (3) insights into molecular mechanisms by which BCAA and other identified microbial products influence metabolic health during childhood and adolescence. These new resources, technologies, and mechanistic insights will have a positive impact by advancing the long-term objective of reducing adolescent obesity and developing effective, durable therapeutics.

项目概要 当前肥胖和胰岛素抵抗在整个生命周期中的流行给公共卫生带来了巨大的影响 挑战。人类观察研究和动物模型粪便移植研究（都主要是 专注于成人）发现肥胖、胰岛素抵抗和微生物群之间存在相互关联。 由于流行病学表明肥胖的发生源于童年，因此迫切需要 了解儿童肥胖的机制并开发预测、预防和治疗儿童肥胖的工具 治疗。严重肥胖的儿童在代谢和发育方面模仿成人表型 心血管风险，但仍处于疾病的最早阶段，严重的共病越来越少 状况。因此，肥胖儿童提供了一个独特的机会和一个理想的人群，可以在其中获得 更深入地了解与肥胖相关的微生物组。为了实现这种见解，本提案的目标 是建立一个综合的研究资源来定义微生物调控的机制 肥胖青少年（12-18 岁）减肥干预前后的宿主代谢。这 拟议的研究利用了杜克大学独特且完善的儿童肥胖干预计划 和胰岛素抵抗。我们之前的研究应用代谢组学技术揭示了血液代谢物 例如支链氨基酸 (BCAA) 与成年后的胰岛素敏感性呈负相关 减肥干预措施，我们已经使用了限生小鼠来证明它们与 微生物群介导的体重增加。我们的初步研究表明支链氨基酸和相关代谢物也 与青少年的胰岛素抵抗和体重增加有关。我们的中心假设是人类肠道 细菌通过改变宿主代谢来控制青少年的宿主体重增加和胰岛素抵抗。这 假设将在两个具体目标中进行检验： 目标 1. 开发资源来定义之间的关联 肠道微生物群和参加门诊体重的严重肥胖青少年群体 管理干预计划。目标 2. 明确人类肠道的分子机制 细菌调节与儿童肥胖相关的代谢特征。完成这项工作将提供三个关键 可供科学界广泛使用的资源：(1) 临床样本、微生物菌株和数据 来自独特的儿科体重管理干预队列的存储库，（2）一套全面的强大的 遗传、分子分析和表型分析技术将产生对微生物的独特见解 控制体重和对肥胖干预反应的社区，以及（3）对分子的见解 BCAA 和其他已鉴定的微生物产物影响代谢健康的机制 童年和青春期。这些新的资源、技术和机制见解将产生积极的影响 通过推进减少青少年肥胖的长期目标并制定有效、持久的措施来产生影响 疗法。