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

项目总结 肠道微生物代谢物已成为人类心脏代谢健康的关键因素。在我们的初步研究中， 三甲胺氮氧化物(TMAO)和马儿酚，两种饮食衍生的肠道微生物代谢物，与 即使在调整了传统的冠心病风险因素后，也是如此。这些发现，在 与越来越多的关于肠道微生物代谢对人类心脏代谢健康的重要性的文献相一致， 导致我们的假设，肠道微生物代谢物可能是新的生物标志物和/或治疗靶点 预防冠心病。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 系统研究肠道微生物代谢产物与冠心病风险的关系，随后进行严格验证 以及潜在的饮食-微生物-宿主相互作用的评估。此外，只有几项研究检查了 非白人人群，特别是携带A基因的非裔美国人的代谢谱与冠心病风险的关系 冠心病负担高得不成比例。对于人类肠道微生物区系研究，来自不同种群的数据 种族/民族、地理区域和习惯饮食对于确定因果关系是非常有价值的， 潜在生物标志物的概括性和临床实用性，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物与冠心病风险的关系。 来自NIH资助的、基于人口的五个预期队列：南方社区队列研究(SCCS)， 上海女性和男性健康研究(SWMHS)，动脉粥样硬化多民族研究(MESA)，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 在900对黑人病例对照中检测主要微生物代谢物的半定量分析， 来自SCCS和SWMHS的白人和亚洲人(每种族300对)。目标2(验证)将首先使用现有的 MESA和ARIC中的代谢组学数据进行计算机内验证；然后将确认代谢物 在来自SCCS、SWMHS和MESA的1,150个病例对照对的独立集合中进行量化(每对约400对 种族)。我们将评估这种关联是否因人口统计学而异，以及微生物代谢物是否 可能会改善冠心病风险预测。AIM 3(饮食-微生物-宿主相互作用)将执行一种新的中介- 交互作用分析，以评估膳食纤维(AS)是否以及在多大程度上改变了相关性 益生素)和整体饮食质量，并受血脂异常、高血压和糖尿病的影响或调节。 这将是第一个研究肠道微生物代谢物与风险关系的强有力的多种族研究。 通过对饮食-微生物-宿主相互作用的仔细验证、量化和评估来评估CHD。这项研究将 提高我们对肠道微生物代谢在冠心病病因和差异中的作用的认识，确定新的 生物标志物，并为基于饮食/微生物区系的新干预措施提供信息。我们团队在以下方面有丰富的经验 代谢组学和饮食-微生物区系-冠心病研究，因此，是完成这项研究的独特地位。

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.