Transition to a Western diet and cardiometabolic risk: biomarkers derived from the microbiome

 描述（由申请人提供）：尽管最近出现了肠道微生物群作为影响肥胖和相关代谢紊乱（如糖尿病和心血管疾病）的新因素，但对长期饮食对微生物介导的疾病风险的作用知之甚少。这种缺乏理解的主要原因是：1）缺乏高质量的长期饮食数据与微生物组数据相结合; 2）缺乏环境和结果快速变化的人群的数据，这些数据具有足够的可变性来创建一系列暴露;以及3）没有充分使用复杂的统计模型来检查依赖于时间的复杂系统的每一部分。中国健康与营养调查（CHNS）是一项由美国国立卫生研究院（NIH）资助的研究，对15，000多人进行了25年的随访，提供了高质量的纵向数据，并捕捉了过去二十年中从传统饮食向西方饮食的转变，以及城市化和肥胖和心血管疾病的出现。我们将利用这些数据来产生一些见解，而这些见解在那些只食用西式饮食的受试者的研究中是无法获得的。使用复杂的统计模型，我们建议检查肠道微生物群组成的信息沿着血浆代谢组的数据是否可以预测心脏代谢疾病的标志物（体重指数，中心性肥胖，糖尿病和炎症），使我们能够将微生物群与疾病途径联系起来。我们建议在2015年的考试中从10，000名年龄在30-65岁的成年CHNS参与者中收集粪便样本。（贵州，积极城市化，n=500;和湖南，已经城市化，n=500），为了确定西方饮食中的微生物（和长期变化），我们将在16 S V3-V4区域（n= 1，000）中创建微生物序列，并储存剩余（n= 9，000）粪便样本。我们将选择一个具有16 S数据的子样本（n=400），这些子样本在25年内一直食用传统饮食，并对宿主进行血浆代谢组学研究。在具有微生物群加代谢组数据的CHNS子样本（n=400）中，我们将在CHNS 2017中收集重复的血液和粪便样本，以获得16 S和血浆代谢组学数据，以评估饮食，肠道微生物群，血浆代谢物和心脏代谢疾病标志物的两年变化（2015-2017）。我们将研究肠道微生物群和血浆代谢产物是否因25年内饮食变化的时间而异，以及它们是否与健康结果相关。在我们的纵向子样本中，我们将研究西方饮食标志物的变化与微生物多样性和群落组成以及代谢物的同时变化的关系。我们首先使用一系列的标准回归模型，然后进行高维回归分析，并进行变量选择和验证，以建立预测模型。我们利用了一个已经建立的、特征良好的大型队列，其饮食和微生物群落的变异性远远大于仅采用西方饮食的队列研究。拟议的项目将大大改变目前对饮食，肠道微生物群，宿主代谢和心脏代谢疾病交叉的理解。

 DESCRIPTION (provided by applicant): Despite recent emergence of gut microbiota as a novel factor influencing obesity and related metabolic disorders, such as diabetes and cardiovascular disease, very little is known about the role of long-term diet on microbially mediated disease risk. The primary reasons for this lack of understanding are: 1) lack of high quality, long-term diet data in combination with microbiome data; 2) lack of data in populations undergoing rapid changes in environments and outcomes, with enough variability to create a range of exposures; and 3) insufficient use of complex statistical models to allow examination of each piece of the time-dependent, complex system. The China Health and Nutrition Survey (CHNS), an NIH-funded study of more than 15,000 individuals followed over 25 years, provides high quality longitudinal data and captures the transition from traditional to Western diet in parallel with urbanization and emergence of obesity and cardiovascular disease during the past two decades. We will use these data to generate insights that would not be obtainable in studies with subjects who consume only a Westernized diet. Using sophisticated statistical models we propose to examine whether information on gut microbiota composition along with data on the plasma metabolome can predict markers of cardiometabolic disease (body mass index, central adiposity, diabetes and inflammation), allowing us to implicate microbiota in disease pathways. We propose to collect fecal samples from 10,000 adult CHNS participants aged 30-65 at the 2015 exam. In a subsample from two neighboring Southern provinces (Guizhou, actively urbanizing, n=500; and Hunan, already urbanized, n=500) varying in current (and long-term change) in Western diet, we will create microbial sequences in the 16S V3-V4 region (n=1,000) and store the remaining (n=9,000) fecal samples. We will select a subsample with 16S data who have consumed a traditional diet over the 25 years (n=400) and conduct plasma metabolomics of the host. In the CHNS subsample with microbiota plus metabolome (n=400) data, we will collect replicate blood and fecal samples in CHNS2017 to derive 16S and plasma metabolomics data to assess two-year changes (2015-2017) in diet, gut microbiota, plasma metabolites and in markers of cardiometabolic disease. We will examine whether gut microbiota and plasma metabolites differ depending upon when, within the 25-year period, diet changes occur, and if they are associated with health outcomes. In our longitudinal subsample we will examine changes in markers of Western diet in relation to concurrent changes in microbial diversity and community composition, and metabolites. We first use a series of standard regression models and then high dimensional regression analysis with variable selection and validation to build predictive models. We capitalize upon an established and well-characterized, large cohort with far greater variability in diet and microbial communities than studies in cohorts on only Western diets. The proposed project will substantially transform current understanding of the intersection of diet, gut microbiota, host metabolism and cardiometabolic disease.