Gut microbiota and metabolite interactions in atherosclerosis

肠道微生物群和代谢物在动脉粥样硬化中的相互作用

• 批准号: 10063553
• 负责人: Aldons Jake Lusis
• 金额: $ 64.52万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063553
• 关键词: 16S ribosomal RNA sequencing; Affect; Anthocyanins; Atherosclerosis; Bacteria; Biological Models; Blood Circulation; Cardiometabolic Disease; Cardiovascular Diseases; Cecum; Cholesterol; Chromosome Mapping; Collection; Development; Diet; Dietary Component; Disease; Environment; Environmental Impact; Environmental Risk Factor; Exhibits; Genetic; Genetic Screening; Germ-Free; Human; Hybrids; Inbred Strains Mice; Inflammation; Insulin Resistance; Laboratories; Lead; Lesion; Link; Lipids; Mass Spectrum Analysis; Metabolite Interaction; Metagenomics; Microbe; Microbiology; Mus; Obesity; Pathway interactions; Pharmaceutical Preparations; Physiological; Plasma; Population; Predisposition; Production; Research Personnel; Risk Factors; Sampling; Statistical Models; Thrombosis; Validation; Variant; Work; atherosclerosis risk; base; bile acid metabolism; cardiometabolism; case control; cohort; experimental study; genome wide association study; gut microbes; gut microbiota; human microbiota; inflammatory marker; interest; member; metabolome; metabolomics; microbial; microbial composition; microbiome; microbiome analysis; microbiota; microbiota metabolites; mouse model; new therapeutic target; novel; novel therapeutic intervention; skills; trait; trimethyloxamine

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.

项目描述 肠道菌群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生产，饮食 进入循环并影响生理功能的代谢物的成分，例如 炎。我们建议对肠道微生物群的全面屏幕进行全面的屏幕 导致心脏代谢疾病的代谢产物。使用一组遗传多样 小鼠的近交菌株，我们将确定微生物和微生物源代谢物，这些代谢物 与动脉粥样硬化结合，然后在人类人群和机械研究中进行验证 在无菌小鼠中。这项工作将在三个具有免费技能的实验室中完成：A。 Lusis（遗传学），F。Rey（微生物学）和Z. Wang（代谢组学）。所有调查员 一起工作了几年。 该提案代表了我们先前使用A进行的屏幕的扩展 100个小鼠的近交菌株的面板（总计900只小鼠）。在那个屏幕中，我们 观察到在200倍的病变发育范围内。我们现在建议分析 小鼠的微生物组（AIM 1）和血浆代谢组（AIM 2），并将其与 动脉粥样硬化特征。然后，我们将通过在 动脉粥样硬化病例对照人群（AIM 3）。最后，我们将研究机制 代谢物使用无菌小鼠模型影响疾病（AIM 4）。在初步 研究，三甲胺-N-氧化物的水平，另一个微生物衍生的分子显示为 有助于人类动脉粥样硬化，与病变发育显着相关。 而且，使用面板的子集，我们鉴定了两个微生物（A. muciniphila和R. intestinalis） 与心脏代谢性状有关，并表明这些表现出预测的影响 当用来定居小鼠时。 这些初步研究为总体方法提供了强有力的验证。我们 预计确定与动脉粥样硬化和相关的几种新型代谢产物 特征，并探索潜在的机制。这应该为新颖的疗法铺平道路 该靶向微生物组。