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

项目摘要 目前，肥胖和胰岛素抵抗在整个生命周期中的流行病对公众健康造成了巨大的影响。 挑战.人类观察研究和动物模型中的粪便移植研究（两者都很大程度上 主要针对成年人）发现肥胖、胰岛素抵抗和微生物群之间存在相互联系。 由于流行病学指出肥胖的起源是儿童时期，因此迫切需要 了解儿童肥胖的机制，并开发预测，预防和治疗的工具。 治疗患有严重肥胖症的儿童在代谢和肥胖的发展中模仿成人表型。 心血管风险，但处于疾病的最早阶段，合并症较少且不太严重 条件因此，肥胖儿童提供了一个独特的机会和一个理想的人口，其中收集 深入了解肥胖相关的微生物组。为了实现这种见解，本提案的目标是 是建立一个全面的研究资源，以确定微生物调节的机制， 肥胖青少年（12-18岁）在减肥干预前后的宿主代谢。的 一项拟议的研究利用了杜克独特而完善的儿童肥胖干预计划 和胰岛素抵抗。我们先前的研究已经应用代谢组学技术来揭示血液代谢物 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，我们已经使用gnotobiotic小鼠证明他们的积极关联， 微生物介导的体重增加。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。我们的核心假设是人类的肠道 细菌通过改变宿主的新陈代谢来控制宿主的体重增加和青少年的胰岛素抵抗。这 假设将在两个具体目标中进行测试：目标1。开发一个资源来定义 肠道微生物群和严重肥胖的青少年人口登记在门诊体重 管理干预计划。目标二。明确人类肠道疾病的分子机制 细菌调节与儿童肥胖症相关的代谢特征。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）一套全面的鲁棒的 遗传、分子特征分析和表型分析技术，将对微生物 控制体重和对肥胖干预反应的社区，以及（3）对分子生物学的见解 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，技术和机械的见解将有积极的影响。 通过推进减少青少年肥胖的长期目标， 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.