Gut microbiota and metabolite interactions in atherosclerosis

项目描述 肠道微生物群与许多不同的疾病有关，包括 心血管疾病一个常见的机制涉及生产，从饮食 成分，进入循环并影响生理功能的代谢物， 炎症我们建议对肠道微生物来源的 导致心脏代谢紊乱的代谢物。利用一组基因多样的 近交系小鼠，我们将确定微生物和微生物衍生的代谢产物， 与动脉粥样硬化相关，随后在人类队列和机制研究中进行验证 在无菌小鼠中。这项工作将在三个实验室完成，并提供补充技能： Lusis（genetics），F. Rey（微生物学）和Z.王（代谢组学）。所有的调查员 已经一起工作了好几年了。 该建议代表了我们以前使用 一组100只近交系小鼠用于动脉粥样硬化（总共900只小鼠）。在这个屏幕上，我们 观察到超过200倍的病变发展范围。我们现在建议分析 微生物组（目标1）和血浆代谢组（目标2）的小鼠，并将这些与 动脉粥样硬化特征然后，我们将优先考虑的重要协会，研究这些在一个 动脉粥样硬化病例对照人群（目的3）。最后，我们将研究 代谢物通过无菌小鼠模型影响疾病（Aim 4）。初步 研究表明，另一种微生物衍生的分子， 导致人类动脉粥样硬化，与病变发展显著相关。 而且，使用小组的一个子集，我们确定了两种微生物（A。muciniphila和R.（掌声） 与心脏代谢性状相关，并显示这些表现出预测的影响， 当用于殖民小鼠时。 这些初步研究为总体方法提供了有力的验证。我们 预期鉴定与动脉粥样硬化和相关的几种新的代谢物 特征，并探索潜在的机制。这将为新疗法铺平道路 针对微生物组。

Project Description Gut microbiota have been associated with many different disorders, including cardiovascular disease. One common mechanism involves the production, from dietary components, of metabolites that enter the circulation and affect physiologic functions such as inflammation. We propose to perform a comprehensive screen of gut microbiota-derived metabolites that contribute to cardio-metabolic disorders. Using a panel of genetically diverse inbred strains of mice, we will identify microbes and microbiota-derived metabolites that associate with atherosclerosis, followed by validation in human cohorts and mechanistic studies in germ-free mice. The work will be done in three laboratories with complimentary skills: A. Lusis (genetics), F. Rey (microbiology), and Z. Wang (metabolomics). All of the investigators have worked together for several years. The proposal represents an extension of a screen we previously performed using a panel of 100 inbred strains of mice for atherosclerosis (900 mice total). In that screen, we observed over a 200-fold range of lesion development. We now propose to analyze the microbiomes (Aim 1) and plasma metabolomes (Aim 2) of the mice and to relate these to atherosclerosis traits. We will then prioritize the significant associations by studying these in an atherosclerosis case-control human population (Aim 3). Finally, we will study the mechanisms by which the metabolites affect disease using germ-free mouse models (Aim 4). In preliminary studies, the levels of trimethylamine-N-oxide, another microbe-derived molecule shown to contribute to human atherosclerosis, were significantly correlated with lesion development. And, using a subset of the panel, we identified two microbes (A. muciniphila and R. intestinalis) associated with cardiometabolic traits and showed that these exhibited the predicted effects when used to colonize mice. These preliminary studies provide strong validation for the overall approach. We anticipate identifying several novel metabolites associated with atherosclerosis and related traits, and exploring the underlying mechanisms. This should pave the way for novel therapies that target the microbiome.