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

项目总结 目前肥胖和胰岛素抵抗在人的一生中的大流行给公众健康带来了巨大的威胁。 挑战。动物模型中的人类观察性研究和粪便移植研究(都是主要的 (主要针对成年人)发现了肥胖、胰岛素抵抗和微生物区系之间的相互联系。 由于流行病学指出肥胖的起源源于童年，因此迫切需要 了解儿童肥胖的机制，并开发预测、预防和治疗肥胖的工具。 治疗。严重肥胖的儿童在代谢和发育过程中模仿成人的表型 心血管风险，但处于疾病的早期阶段，合并疾病较少且不太严重 条件。因此，肥胖儿童提供了一个独特的机会和理想的人群 对与肥胖相关的微生物群有更深入的了解。为了使这种洞察力成为可能，本提案的目标是 是建立一个全面的研究资源来定义潜在的微生物调节机制 肥胖青少年(12-18岁)减肥干预前后的宿主代谢。这个 拟议的研究利用杜克大学独特而成熟的儿童肥胖症干预计划 和胰岛素抵抗。我们之前的研究已经应用代谢组学技术揭示了血液代谢物 如支链氨基酸(BCAA)与成年后胰岛素敏感性呈负相关 减肥干预措施，我们已经使用诺生菌小鼠来证明它们与 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直觉 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 登记在门诊体重中的严重肥胖青少年的肠道微生物区系 管理干预计划。目的2.定义人类肠道的分子机制 细菌调节与儿童肥胖有关的代谢特征。这项工作的完成将提供三个关键 供科学界广泛使用的资源：(1)临床样本、微生物群菌株和数据 来自独特的儿科体重管理干预队列的存储库，(2)全面的强健套件 遗传、分子图谱和表型分析技术，将产生对微生物的独特见解 控制体重和对肥胖干预的反应的社区，以及(3)对分子的洞察 支链氨基酸和其他已确定的微生物产品在 童年和青春期。这些新的资源、技术和机械的洞察力将产生积极的影响 通过推进减少青少年肥胖和发展有效、持久的长期目标所产生的影响 治疗学。

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.