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: 10308700
• 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 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308700
• 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 一起工作了好几年 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。

项目成果

The Nutritional Supplement L-Alpha Glycerylphosphorylcholine Promotes Atherosclerosis.

• DOI: 10.3390/ijms222413477
• 发表时间: 2021-12-15
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Wang Z;Hazen J;Jia X;Org E;Zhao Y;Osborn LJ;Nimer N;Buffa J;Culley MK;Krajcik D;van den Born BH;Zwinderman K;Levison BS;Nieuwdorp M;Lusis AJ;DiDonato JA;Hazen SL
• 通讯作者: Hazen SL

Identification of the Transcription Factor ATF3 as a Direct and Indirect Regulator of the LDLR.

• DOI: 10.3390/metabo12090840
• 发表时间: 2022-09-06
• 期刊: Metabolites
• 影响因子: 4.1
• 作者: Bauer S;Eigenmann J;Zhao Y;Fleig J;Hawe JS;Pan C;Bongiovanni D;Wengert S;Ma A;Lusis AJ;Kovacic JC;Björkegren JLM;Maegdefessel L;Schunkert H;von Scheidt M
• 通讯作者: von Scheidt M

Gene-Environment Interactions for Cardiovascular Disease.

• DOI: 10.1007/s11883-021-00974-9
• 发表时间: 2021-10-14
• 期刊: Current atherosclerosis reports
• 影响因子: 5.8
• 作者: Hartiala JA;Hilser JR;Biswas S;Lusis AJ;Allayee H
• 通讯作者: Allayee H

Machine Learning Reveals Time-Varying Microbial Predictors with Complex Effects on Glucose Regulation.

• DOI: 10.1128/msystems.01191-20
• 发表时间: 2021-02-16
• 期刊: mSystems
• 影响因子: 6.4
• 作者: Aasmets O;Lüll K;Lang JM;Pan C;Kuusisto J;Fischer K;Laakso M;Lusis AJ;Org E
• 通讯作者: Org E

Individual diet has sex-dependent effects on vertebrate gut microbiota.

• DOI: 10.1038/ncomms5500
• 发表时间: 2014-07-29
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Bolnick, Daniel I.;Snowberg, Lisa K.;Hirsch, Philipp E.;Lauber, Christian L.;Org, Elin;Parks, Brian;Lusis, Aldons J.;Knight, Rob;Caporaso, J. Gregory;Svanback, Richard
• 通讯作者: Svanback, Richard