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: 10016253
• 负责人: John F Rawls
• 金额: $ 137.3万
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10016253
• 关键词: Adolescence; Adolescent; Adolescent obesity; Adult; Age; Animal Model; Bacteria; Blood; Body Weight; Branched-Chain Amino Acids; Child; Childhood; Clinical; Communities; Coronary heart disease; Data; 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; Link; Longevity; Mediating; Metabolic; Metabolism; Methods; Microbe; Microbiology; Mission; Molecular; Molecular Profiling; Morbid Obesity; Mus; Muscle; North Carolina; Obesity; Observational Study; Outcome; Outpatients; Pathway Analysis; Patients; Pediatric cohort; Peripheral Blood Mononuclear Cell; Phenocopy; Phenotype; Plant Roots; Plasma; Population; Prevention; Production; Public Health; Regulation; Research; Resources; Risk; Sampling; Specimen; Technology; Testing; Therapeutic; Thinness; Treatment Efficacy; Treatment outcome; United States National Institutes of Health; Weight Gain; Weight maintenance regimen; Work; Youth; acylcarnitine; adult obesity; analysis pipeline; bacterial genetics; base; cardiovascular risk factor; cohort; comorbidity; data warehouse; disadvantaged population; effective therapy; experimental study; fatty acid oxidation; fecal microbiota; fecal transplantation; genetic analysis; gut bacteria; gut microbiota; improved; innovation; insight; insulin sensitivity; intervention program; metabolic profile; metabolomics; microbial; microbial community; microbiome; microbiome research; microbiota; multidimensional data; novel; novel strategies; obesity in children; obesity treatment; pandemic disease; 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.

项目摘要 整个生命周期的肥胖和胰岛素抵抗的当前大流行呈现出巨大的公共卫生 挑战。人类的观察研究和动物模型中的粪便移植研究（都在很大程度上 专注于成年人）发现肥胖，胰岛素抵抗和微生物群之间存在相互作用。 因为流行病学指出了肥胖起源的童年起源，所以迫切需要 了解小儿肥胖的机制，并为其预测，预防和 治疗。严重肥胖的儿童模仿成人表型在代谢和 心血管风险，但处于疾病的最早阶段，合并症较少和不那么严重 状况。肥胖的孩子带来了独特的机会和理想的人口 对肥胖相关的微生物组的深入了解。为了实现此类见解，该提议的目的 是建立一个全面的研究资源，以定义微生物调节的基础机制 减肥干预前后，肥胖症青少年（12-18岁）的宿主代谢。这 拟议的研究利用了杜克大学独特且公认的小儿肥胖干预计划 和胰岛素抵抗。我们先前的研究已应用代谢组技术来揭示血液代谢产物 例如分支链氨基酸（BCAA）与成人后的胰岛素敏感性负相关 减肥干预措施，我们已经使用了gnotobiotic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，BCAA和相关代谢物也是 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的肠道 细菌通过修饰宿主代谢来控制青少年的宿主体重增加和胰岛素抵抗。这 假设将以两个具体的目的进行检验：目标1。开发一种资源来定义关联 肠道菌群和严重肥胖的青少年种群参加门诊体重 管理干预计划。目标2。定义人类肠道的分子机制 细菌调节与小儿肥胖有关的代谢特征。这项工作的完成将提供三个关键 科学界广泛使用的资源：（1）临床样本，微生物群菌株和数据 独特的小儿体重管理干预队列的存储库，（2）一套综合的稳健套件 遗传，分子分析和表型技术，这些技术将对微生物产生独特的见解 控制体重和对肥胖干预的反应的社区，以及（3）对分子的见解 BCAA和其他确定的微生物产品会影响代谢健康的机制 童年和青少年。这些新的资源，技术和机械见解将具有积极的 通过促进减少青少年对象并发展有效，耐用的长期目标来影响 疗法。