A Novel Gut Microbial-Dependent Nutrient Metabolite and Atherosclerosis

 描述(由申请人提供)：饮食是一种可改变的心血管疾病(CVD)风险因素，也是以人群为基础的心血管疾病预防方法的核心组成部分。然而，什么构成心血管健康的最佳饮食的确切性质还存在争议。迫切需要进行研究，描绘饮食反应异质性的生物学来源，这些异质性得到了很好的证明，但却鲜为人知。肠道细菌与营养吸收和新陈代谢密切相关，但直到最近，我们还缺乏在大规模研究中有效描述整个微生物组的工具。一项新的工作支持了一种机制，即通过肠道微生物依赖的方式将饮食中的胆碱或L肉碱代谢成三甲胺N氧化物，从而增加心血管疾病风险。这些发现受到了极大的关注，因为它们可能指向通过饮食或有针对性的益生菌/益生菌进行的干预；它们也提出了关于TMAO前体对心血管疾病风险的影响的问题。然而，从饮食到心血管疾病通过微生物产生TMAO的途径还没有在基于人群的样本中进行研究。我们建议在一项基于人群的前瞻性流行病学研究中研究这一途径：青年成人冠状动脉风险发展(CARDIA)研究，对5115名个体进行了超过25年的跟踪调查(1985/86基线；年龄18-30岁)。我的长期职业目标是建立一个独立的研究项目，致力于了解个体对饮食代谢反应的变异性与心血管疾病风险的关系。为此，我寻求将 我在流行病学、饮食、营养和生物统计分析方面的专业知识，以及在肠道微生物组和人类新陈代谢-饮食反应可变性的关键生物成分-方面的实质性培训，以及在生物信息学和高维数据分析统计方法方面的技术培训。我的长期职业目标是建立一个外部资助的合作研究计划，将流行病学与与高维数据和翻译科学相关的新方法和技术进步联系起来。我的科学目标是确定个体水平的代谢变异性通过肠道微生物对营养吸收和新陈代谢的作用，在多大程度上影响饮食对心血管疾病的影响。我的中心假设是，心血管疾病的饮食风险因素部分地受到肠道微生物群落组成和功能的调节。我组建了一支出色的导师团队，他们擅长以下方面：人体新陈代谢、营养生物化学和代谢组学(Zeisel)；跨学科研究，并将高维度生物数据(基因组学)整合到流行病学研究中(Gordon-Larsen)；肠道微生物组生物学和肠道微生物组数据的生物信息学分析(Fodor)；高维数据统计分析(Sun)；以及多中心队列研究中辅助病例队列研究的设计(Heiss)。职业发展和研究活动将最终成功竞争R01，以研究肠道微生物途径的异质饮食反应，特别是在大规模流行病学研究中关于心血管系统的研究。

 DESCRIPTION (provided by applicant): Diet is a modifiable cardiovascular disease (CVD) risk factor and a core component of population-based approaches for CVD prevention. Yet, the exact nature of what constitutes an optimal diet for cardiovascular health is debated. There is a critical need for studies that delineate the biologic sources of well-documented, but poorly understood heterogeneity in diet responsiveness. Gut bacteria are intimately involved in nutrient absorption and metabolism, but until recently we lacked the tools to efficiently characterize the whole microbiome in large-scale studies. New work supports a mechanism for increased CVD risk through gut microbial-dependent metabolism of dietary choline or L-carnitine to trimethylamine N-oxide (TMAO). These findings have received much attention as they may point to interventions through diet or targeted pro/pre- biotics; they have also raised questions about the impact of TMAO precursors on CVD risk. However, the pathway from diet to CVD through microbial production of TMAO has not been studied in population-based samples. We propose to study this pathway in a population-based prospective epidemiologic study: the biracial (black/white) Coronary Artery Risk Development in Young Adults (CARDIA) study of 5,115 individuals followed over 25 years (baseline 1985/86; aged 18-30). My long-term career goal is to build an independent research program dedicated to understanding individual variability in metabolic response to diet in relation to CVD risk. To this end, I seek to integrate my expertise in epidemiology, diet, nutrition, and biostatistical analysis, with substantive trainig in gut microbiome and human metabolism-key biologic components of variability in dietary response-and technical training in bioinformatics and statistical approaches to high-dimensional data analysis. My long-term career goal is to build an externally-funded, collaborative research program that bridges epidemiology with new methodologic and technologic advances related to high-dimensional data and translational science. My scientific aim is to determine the extent to which individual-level metabolic variability plays a role in dietary effects on CVD through gut microbial functions on nutrient absorption and metabolism. My central hypothesis is that dietary risk factors for CVD are partially mediated by gut microbial community composition and function. I have assembled an outstanding team of mentors, with expertise in human metabolism, nutritional biochemistry, and metabolomics (Zeisel); trans-disciplinary research and integration of high-dimensional biologic data (genomics) into epidemiologic studies (Gordon-Larsen); gut microbiome biology and bioinformatics analysis of gut microbiome data (Fodor); statistical analysis of high-dimensional data (Sun); and the design of ancillary case- cohort studies within multi-center cohort studies (Heiss). Career development and research activities will culminate in successfully competing for an R01 to study gut microbial pathways for heterogeneous diet responsiveness, particularly with respect to the cardiovascular system in a large-scale epidemiologic study.