Clinical, genetic and cardiometabolic risk correlates of the gut microbiome

 描述(申请人提供)：动脉粥样硬化性心血管疾病(CVD)、2型糖尿病(T2D)和代谢综合征(METS)造成巨大的公共负担，这种负担将随着肥胖率的增长而加速。这些情况都属于促炎状态，但共同的潜在机制仍不清楚。肠道中的共生微生物群落已经成为炎症、免疫功能和新陈代谢的调节器。先天免疫成分的基因敲除可以概括Met的许多方面，这些方面是由改变的微生物群介导的。在人类疾病队列中的研究表明，找到与CVD、T2D和METS相关的微生物谱是可行的，并涉及微生物代谢的特定途径(例如，短链脂肪酸[SCFA]和三甲胺-N-氧化物[TMAO]的生物合成)，这些途径与饮食相互作用，可能调节炎症、代谢以及CVD、METS和T2D的风险。然而，我们对这些途径如何与微生物分类和功能、宿主途径和环境(如饮食)相互作用的理解仍然不完整。这一提议的总体假设是，肠道微生物区系的功能可能为CVD、Mets和T2D中观察到的许多重叠的代谢和炎症表型提供一种统一的机制。具体地说，我们将测试有关SCFA和TMAO途径作用的重点假说，包括它们与微生物物种和功能、饮食、宿主基因以及CVD、Mets和T2D的关系。我们还将对微生物区系组成和功能与心血管疾病、蛋氨酸和T2D的关系进行二次、公正的分析。我们将在弗雷明翰心脏研究(FHS)的Gen3和Omni2队列中测试这些假设，这是一个包括3800名男性和女性的中年、多种族、社区样本。在目标1中，我们将使用16S rRNA基因序列和计算的微生物途径/功能信息来检验关于粪便SCFA和血浆TMAO水平与肠道微生物种类和功能、饮食以及流行的心血管疾病、蛋氨酸和T2D之间关系的假设。在目标2中，我们将确定影响：(A)粪便SCFA和血浆TMAO水平的宿主基因，(B)与粪便SCFA或血浆TMAO相关的微生物分类群/功能，以及(C)与流行的心血管疾病、蛋氨酸或T2D相关的分类群/功能(同时确定这些疾病的共同或专有宿主特征)。在目标3中，我们将测试在基线和靠近心血管事件或蛋氨酸中毒事件附近的粪便样本的后基因组、后转录和代谢组学微生物群是否提供额外的机制洞察力。了解特定的微生物途径如何与饮食、宿主基因和疾病风险相关，最终可能导致调节微生物功能或宿主-微生物功能相互作用的新疗法。这项应用将FHS的基因类型、表型和心血管疾病和代谢性疾病方面的专业知识与一个在人类微生物组项目中经验丰富的团队结合在一起，并从微生物组研究中获得生物医学见解。这项研究的数据将成为社区资源，并有利于更广泛社区的微生物区系研究。

 DESCRIPTION (provided by applicant): Atherosclerotic cardiovascular disease (CVD), type 2 diabetes (T2D) and metabolic syndrome (MetS) exert a huge public burden that will accelerate with the growing rates of obesity. These conditions share a pro- inflammatory state, yet shared underlying mechanisms remain unclear. The community of commensal microbes that reside in the gut has emerged as a modulator of inflammation, immune function and metabolism. Genetic knockout of innate immune components can recapitulate many aspects of MetS that are mediated by altered microbiota. Studies in human disease cohorts show the feasibility of finding microbial profiles associated with CVD, T2D and MetS, and implicate specific pathways of microbial metabolism (e.g., biosynthesis of short-chain fatty acids [SCFA] and trimethylamine-N-oxide [TMAO]) that interact with diet and may modulate inflammation, metabolism, and risk of CVD, MetS and T2D. However, our understanding of how these pathways interact with microbial taxonomy and function, host pathways and environment (e.g., diet) remains incomplete. The overall hypothesis of this proposal is that the function of the gut microbiota may provide a unifying mechanism for many of the overlapping metabolic and inflammatory phenotypes observed in CVD, MetS and T2D. Specifically, we will test focused hypotheses about the roles of the SCFA and TMAO pathways, including their relation to microbial species and function, diet, host genotype, and CVD, MetS and T2D. We will also pursue secondary, unbiased analyses into the association of microbiota composition and function with CVD, MetS and T2D. We will test these hypotheses in the Framingham Heart Study (FHS) Gen3 and Omni2 cohorts, a middle-aged, multi-ethnic, community-based sample of 3800 men and women. In Aim 1, we will use 16S rRNA gene sequence and calculated microbial pathway/functional information to test hypotheses about the relation of stool SCFA and plasma TMAO levels to gut microbial species and function, diet, and prevalent CVD, MetS and T2D. In Aim 2, we will identify host genes that influence: (a) stool SCFA and plasma TMAO levels, (b) microbial taxa/functions associated with stool SCFA or plasma TMAO, and (c) taxa/functions associated with prevalent CVD, MetS or T2D (while identifying host features shared vs. private to more than one of these diseases). In Aim 3, we will test whether meta-genomic, metatranscriptomic and metabolomics microbiota profiles of stool samples at baseline and in close proximity to incident CVD or MetS confer additional mechanistic insights. Understanding how specific microbial pathways relate to diet, host genes, and disease risk may ultimately lead to novel therapies that modulate microbial function or host- microbe functional interactions. This application combines FHS genotypes, phenotypes and expertise in CVD and metabolic disease with a team experienced in the Human Microbiome Project and drawing biomedical insights from microbiome studies. The data from this study will be a community resource and benefit microbiota studies in the broader community.