Gut microbiota and metabolite interactions in atherosclerosis

项目说明 肠道微生物区系与许多不同的疾病有关，包括 心血管疾病。一种常见的机制涉及到从饮食中产生 代谢产物中进入循环并影响生理功能的成分，如 发炎。我们建议对肠道微生物区系进行全面筛查 导致心脏代谢紊乱的代谢物。使用一个遗传多样性的小组 近亲繁殖的小鼠品系，我们将鉴定微生物和微生物区系衍生的代谢物 与动脉粥样硬化有关，随后在人类队列和机制研究中进行验证 在无菌小鼠身上。这项工作将在三个实验室进行，技能互补：A. Lusis(遗传学)、F.Rey(微生物学)和Z.Wang(代谢组学)。所有的调查人员 已经在一起工作了几年。 该提案代表了我们之前使用 由100只近交系小鼠组成的动脉粥样硬化小组(总共900只小鼠)。在该屏幕中，我们 观察到了超过200倍的病变发展范围。我们现在建议分析 小鼠的微生物群(Aim 1)和血浆代谢体(Aim 2)，并将其与 动脉粥样硬化的特征。然后我们将通过研究这些重要关联来确定它们的优先顺序 动脉粥样硬化病例对照人群(目标3)。最后，我们将对这些机制进行研究 代谢产物通过无菌小鼠模型影响疾病(目标4)。在预赛中 研究表明，另一种微生物来源的分子三甲胺-N-氧化物的水平 对人类动脉粥样硬化的贡献，与病变的发展显著相关。 而且，使用该小组的一个子集，我们鉴定了两种微生物(粘液弧菌和肠杆菌)。 与心脏代谢特征有关，并表明这些特征显示出预期的效果 当被用来定植老鼠的时候。 这些初步研究为总体方法提供了强有力的验证。我们 预期确定几种与动脉粥样硬化相关的新代谢物和相关 特征，并探索潜在的机制。这应该为新的疗法铺平道路。 以微生物群为目标。

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.