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

基本信息

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
项目类别：
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

项目摘要

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.

项目描述肠道微生物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从饮食中产生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进行全面筛查导致心脏代谢紊乱的代谢物。使用一组遗传多样性近交系小鼠，我们将鉴定微生物和微生物群衍生的代谢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。这项工作将在三个具有互补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）。所有调查人员已经合作多年了。该提案代表了我们之前使用的屏幕的扩展由 100 只近交系小鼠组成的小组，用于治疗动脉粥样硬化（总共 900 只小鼠）。在那个画面中，我们观察到超过 200 倍范围的病变发展。我们现在建议分析小鼠的微生物组（目标 1）和血浆代谢组（目标 2），并将它们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优先考虑这些关联动脉粥样硬化病例对照人群（目标 3）。最后我们来研究一下机制使用无菌小鼠模型，代谢物通过其影响疾病（目标 4）。在初步研究显示，另一种微生物衍生分子三甲胺-N-氧化物的水平有助于人类动脉粥样硬化，与病变发展显着相关。并且，使用该小组的一个子集，我们鉴定了两种微生物（A. muciniphila 和 R. Enteris）与心脏代谢特征相关，并表明这些特征表现出预测的效果当用于定殖小鼠时。这些初步研究为整体方法提供了强有力的验证。我们预计鉴定出几种与动脉粥样硬化相关的新代谢物特征，并探讨其潜在机制。这将为新疗法铺平道路以微生物组为目标。