Gut microbial metabolites and risk of coronary heart disease: a prospective, multiethnic, metabolomic study

项目摘要 肠道微生物代谢产物已成为人类心脏代谢健康的关键参与者。在我们的试点研究中， 三甲胺N-氧化物（TMAO）和雌马酚，两种饮食来源的肠道微生物代谢产物，与 冠心病（CHD）的风险，即使在调整了传统的CHD危险因素。这些发现，在 与越来越多的关于肠道微生物代谢在人类心脏代谢健康中的重要性的文献相一致， 我们假设肠道微生物代谢物可能是新的生物标志物和/或治疗靶点， 冠心病预防。然而，据我们所知，还没有基于人群的前瞻性研究应用代谢组学 系统地研究肠道微生物代谢产物与冠心病风险的关系， 和评价潜在的饮食-微生物群-宿主相互作用。此外，只有少数研究检查了 非白人人群中与CHD风险相关的代谢组学特征，特别是非裔美国人， 不成比例的CHD负担。对于人类肠道微生物群研究，来自不同人群的数据 种族/民族、地理区域和习惯性饮食对于确定因果关系非常有价值， 普遍性和潜在生物标志物的临床效用，但目前缺乏。 我们建议通过利用资源来评估循环微生物代谢产物与冠心病风险的关系 来自五个NIH资助的、基于人群的前瞻性队列研究：南方社区队列研究（SCCS）， 上海女性和男性健康研究（SWMHS），多种族动脉粥样硬化研究（梅萨），以及 社区动脉粥样硬化风险研究（ARIC）。我们的研究有三个目标：目标1（发现）将使用 半定量测定法检测900对黑人病例-对照中的主要微生物代谢物组， 白人和亚洲人（每个种族300对）来自SCCS和SWMHS。目标2（验证）将首先使用现有的 梅萨和ARIC中的代谢组学数据进行计算机验证;然后将确认的代谢物 在来自SCCS、SWMHS和梅萨的1，150个病例对照对的独立组中进行定量（每个病例对照组约400对）。 种族）。我们将评估这种关联是否因人口统计学而异，以及微生物代谢产物是否 可能改善CHD风险预测。目标3（饮食-微生物群-宿主相互作用）将进行一种新的调解- 交互作用分析，以评估膳食纤维是否以及在多大程度上改变了这种关联（如 益生元）和整体饮食质量，并由血脂异常、高血压和糖尿病改变或介导。 这将是第一项检查肠道微生物代谢物与风险关系的有力的多种族研究 通过仔细验证、量化和评估饮食-微生物群-宿主相互作用，本研究将 推进我们对肠道微生物代谢在CHD病因学和差异中的作用的认识， 生物标志物，并告知新的饮食/微生物群为基础的干预措施。我们的团队拥有丰富的经验， 代谢组学和饮食微生物群-CHD研究，因此，独特的定位来完成这项研究。

PROJECT SUMMARY Gut microbial metabolites have emerged as key players in human cardiometabolic health. In our pilot studies, trimethylamine N-oxide (TMAO) and equol, two diet-derived gut microbial metabolites, were associated with risk of coronary heart disease (CHD), even after adjusting for traditional CHD risk factors. These findings, in line with a growing literature on the importance of gut microbial metabolism in human cardiometabolic health, led to our hypothesis that gut microbial metabolites may be novel biomarkers and/or therapeutic targets for CHD prevention. Yet, to our knowledge, no population-based, prospective studies have applied metabolomics to systematically investigate gut microbial metabolites in relation to risk of CHD, followed by rigorous validation and evaluation of potential diet-microbiota-host interactions. Moreover, only a few studies have examined metabolomic profiles in relation to CHD risk in non-white populations, especially African Americans who bear a disproportionately high burden of CHD. For human gut microbiota research, data from populations of different races/ethnicities, geographic areas, and habitual diets are extremely valuable for determining the causality, generalizability, and clinical utility of potential biomarkers, but are currently lacking. We propose to evaluate circulating microbial metabolites in relation to risk of CHD by leveraging resources from five NIH-funded, population-based, prospective cohorts: The Southern Community Cohort Study (SCCS), Shanghai Women's and Men's Health Studies (SWMHS), Multi-Ethnic Study of Atherosclerosis (MESA), and Atherosclerosis Risk in Communities Study (ARIC). Our study has three aims: Aim 1 (discovery) will use a semi-quantitative assay that detects major groups of microbial metabolites in 900 case-control pairs of blacks, whites, and Asians (300 pairs per race) from the SCCS and SWMHS. Aim 2 (validation) will first use existing metabolomics data in the MESA and ARIC to perform an in-silico validation; confirmed metabolites will then be quantified in an independent set of 1,150 case-control pairs from SCCS, SWMHS, and MESA (~400 pairs per race). We will evaluate whether the associations vary by demographics, and whether microbial metabolites may improve CHD risk prediction. Aim 3 (diet-microbiota-host interaction) will perform a novel mediation- interaction analysis to evaluate whether and to what extent the associations are modified by dietary fiber (as prebiotics) and overall diet quality and modified or mediated by dyslipidemia, hypertension, and diabetes. This will be the first well-powered, multi-ethnic study examining gut microbial metabolites in relation to risk of CHD with careful validation, quantification, and evaluation of diet-microbiota-host interactions. This study will advance our knowledge of the role of gut microbial metabolism in CHD etiology and disparities, identify new biomarkers, and inform novel diet/microbiota-based interventions. Our team has extensive experience in metabolomics and diet-microbiota-CHD research, and thus, is uniquely positioned to accomplish this study.