Clinical, genetic and cardiometabolic risk correlates of the gut microbiome

肠道微生物组的临床、遗传和心脏代谢风险相关

• 批准号: 9036148
• 负责人: Vasan S Ramachandran
• 金额: $ 91.4万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9036148
• 关键词: Activities of Daily Living; Affect; Anabolism; Atherosclerosis; Bacteria; Bacterial Genes; Biological; Blood; C-reactive protein; Cardiovascular Diseases; Clinical; Cohort Studies; Communities; Data; Development; Diabetes Mellitus; Diagnosis; Diet; Disease; Environment; Feces; Framingham Heart Study; Future; Generations; Genes; Genetic; Genetic Risk; Genome; Genomics; Genotype; Heart Diseases; Human; Human Microbiome; Immune; Immunity; Incidence; Inflammation; Inflammatory; Knock-out; Lead; Measures; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Metagenomics; Microbe; Microbial Taxonomy; Minority; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Onset of illness; Participant; Pathway interactions; Phenotype; Plasma; Prevalence; Prevention; Probiotics; Resources; Risk; Risk Factors; Role; Sampling; TLR5 gene; Taxon; Testing; Transcript; Variant; Volatile Fatty Acids; Woman; base; cardiometabolic risk; cardiovascular disorder risk; clinical risk; cohort; commensal microbes; disorder risk; experience; gut microbiome; gut microbiota; human disease; immune function; insight; men; metabolomics; microbial; microbial community; microbiome; microbiota; middle age; novel; novel strategies; novel therapeutic intervention; novel therapeutics; prebiotics; public health relevance; rRNA Genes; repository; trait; trimethyloxamine

 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.

 描述（由申请人提供）：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）给公众带来了巨大的负担，并且随着肥胖率的不断上升，这些疾病都具有促炎症状态，然而，共同的潜在机制仍不清楚。肠道内的共生微生物群落已成为炎症、免疫功能和新陈代谢的调节剂。先天免疫成分的基因敲除可以概括炎症、免疫功能和新陈代谢的许多方面。由改变的微生物群介导的 MetS。对人类疾病队列的研究表明寻找与 CVD、T2D 和 MetS 相关的微生物谱的可行性，并暗示微生物代谢的特定途径（例如，短链脂肪酸 [SCFA] 和三甲胺的生物合成） -N-氧化物 [TMAO]）与饮食相互作用，可能调节炎症、代谢以及 CVD、MetS 和 T2D 的风险。微生物分类和功能、宿主途径和环境（例如饮食）仍然不完整。该提议的总体假设是肠道微生物群的功能可能为 CVD 中观察到的许多重叠的代谢和炎症表型提供统一的机制。具体来说，我们将测试有关 SCFA 和 TMAO 途径作用的重点假设，包括它们与微生物物种和功能、饮食、宿主基因型以及 CVD、MetS 和 T2D 的关系。我们还将对微生物群组成和功能与 CVD、MetS 和 T2D 之间的关联进行二次、公正的分析，我们将在弗雷明汉心脏研究 (FHS) Gen3 和 Omni2 队列（一个中年、多种族、基于社区的 3800 名男性和女性样本在目标 1 中，我们将使用 16S rRNA 基因序列和计算的微生物途径/功能信息来检验有关粪便 SCFA 关系的假设。和血浆 TMAO 水平对肠道微生物种类和功能、饮食以及流行的 CVD、MetS 和 T2D 的影响。在目标 2 中，我们将确定影响以下因素的宿主基因：(a) 粪便 SCFA 和血浆 TMAO 水平，(b) 微生物分类群/功能。与粪便 SCFA 或血浆 TMAO 相关，以及 (c) 与流行的 CVD、MetS 或 T2D 相关的分类群/功能（同时确定与其中一种以上疾病共有或私有的宿主特征）。目标 3，我们将测试基线和接近 CVD 或 MetS 事件的粪便样本的宏基因组、宏转录组和代谢组学微生物群谱是否能提供额外的机制见解，了解特定的微生物途径与饮食、宿主基因和疾病风险的关系。可能最终会产生调节微生物功能或宿主-微生物功能相互作用的新疗法。该应用将 FHS 基因型、表型以及 CVD 和代谢疾病方面的专业知识与人类微生物组项目经验丰富的团队结合起来。从微生物组研究中汲取生物医学见解。这项研究的数据将成为社区资源，并有益于更广泛社区的微生物群研究。