Levels of trimethylamine metabolites and their associations with dietary intakes and cardiometabolic biomarkers: the TMAO Pooling Project

项目摘要 越来越多的人认识到，饮食-肠道微生物群的相互作用在人类健康中起着重要作用。 心血管健康最近的研究发现了一种饮食来源的肠道微生物群依赖性代谢物， 三甲基胺N-氧化物（TMAO），这可能会促进心血管疾病（CVD）的发展。到目前为止， 在一般人群中只有少数的小规模研究已经调查了这种新的TMAO-CVD途径。有限 证据表明TMAO的产生和代谢受饮食和非饮食因素的影响， 由于TMAO食物的显著差异，饮食与TMAO的关系可能因人群而异 源（例如，肉类vs.鱼类vs.植物性食物）。大规模的流行病学合作研究，包括 种族和地区不同的人群，并纳入饮食，TMAO代谢物， 和CVD生物标志物将为这一元生物途径提供重要的见解，并可能为 开发基于饮食-肠道微生物群相互作用的CVD预防和治疗新策略。 我们建议进行一项大型的国际合作研究：TMAO汇集项目。将 主要基于新成立的代谢组学研究联盟（COMETS），还将包括 其他一些基于人口的研究。截至2017年10月，我们已经从美国，欧洲， 共有44，164名参与者，其中包括51%的女性和46%的未充分研究的种族/民族 组（即，黑人、西班牙裔/拉丁裔和亚洲人）。我们的具体目标是：1）检查分布 TMAO和相关代谢物（即，胆碱、肉毒碱和甜菜碱）在不同年龄、性别、地区 种族/民族、肥胖、吸烟状况和代谢性疾病状况; 2）评估TMAO与 代谢物与含三甲胺食物摄入量的关系，包括人群间的潜在差异; 和3）评价TMAO代谢物与已知CVD生物标志物（例如，葡萄糖，血脂， 和炎症标志物）。我们假设，TMAO水平可能因变异而在人群中存在差异， 在习惯性饮食和代谢疾病状态，这反过来可能会影响心血管疾病的健康在这些人群中。 这将是第一个大规模，多种族，多国代谢组学研究，利用现有的 数据和联盟资源来研究这种新的饮食-TMAO-CVD途径。这是可行的， 节省时间和成本。获得的知识将有助于阐明分布、影响因素和潜力 TMAO对CVD的影响本研究将为今后研究膳食-肠道菌群的作用奠定基础 不同人群之间CVD发展的相互作用，最终可能导致新的， 通过饮食和/或肠道微生物修饰进行CVD预防和治疗的人群特异性策略。 同时，本研究将建立一个网络，用于CVD研究中新兴主题的合作，例如 肠道微生物群，代谢组学和健康差异，并将促进初级研究人员的职业发展 在这些领域，他们合作，并从高级调查人员和他们的同行学习。

PROJECT SUMMARY There is a growing appreciation that diet-gut microbiota interactions play an important role in human cardiovascular health. Recent studies have discovered a diet-derived, gut microbiota-dependent metabolite, trimethylamine N-oxide (TMAO), which may promote the development of cardiovascular disease (CVD). So far, only a few small studies among general populations have investigated this novel TMAO-CVD pathway. Limited evidence suggests that TMAO production and metabolism is influenced by both dietary and non-dietary factors, and that the diet-TMAO association may vary across populations due to significant variations in TMAO food sources (e.g., meat vs. fish vs. plant foods). Large-scale, collaborative epidemiologic studies that include ethnically and regionally diverse populations and incorporate comprehensive data on diet, TMAO metabolites, and CVD biomarkers will provide critical insights into this meta-organismal pathway and may pave the way for developing new strategies for CVD prevention and treatment based on diet-gut microbiota interactions. We propose to conduct a large, international, collaborative study: the TMAO Pooling Project. It will be primarily based on the newly established Consortium of Metabolomics Studies (COMETS) and will also include several other population-based studies. As of Oct. 2017, we have recruited 18 studies from the US, Europe, and Asia, bringing a total of 44,164 participants, including 51% women and 46% understudied racial/ethnic groups (i.e., blacks, Hispanic/Latinos, and Asians). Our Specific Aims are: 1) to examine distributions of TMAO and related metabolites (i.e., choline, carnitine, and betaine) across populations by age, sex, region, race/ethnicity, obesity, smoking status, and metabolic disease status; 2) to evaluate associations of TMAO metabolites with intakes of trimethylamine-containing foods including potential variations across populations; and 3) to evaluate associations of TMAO metabolites with known CVD biomarkers (e.g., glucose, blood lipids, and inflammatory markers). We hypothesize that TMAO level may differ across populations due to variations in habitual diets and metabolic disease status, which in turn may affect CVD health in these populations. This will be the first, large-scale, multi-ethnic, multi-national metabolomics study that leverages existing data and consortium resources to investigate this novel diet-TMAO-CVD pathway. It is feasible and extremely time- and cost-efficient. Knowledge gained will help elucidate the distribution, influencing factors, and potential effects of TMAO on CVD. This study will lay a foundation for future studies on the role of diet-gut microbiota interactions in the development of CVD among diverse populations, which may eventually lead to new, population-specific strategies for CVD prevention and treatment via dietary and/or gut microbial modifications. Meanwhile, this study will establish a network for collaborations on emerging topics in CVD research such as gut microbiota, metabolomics, and health disparities, and will foster career development of junior investigators in these areas as they collaborate and learn from senior investigators and their peers.