Microbial Trimethylamine Lyases and Atherosclerosis

微生物三甲胺裂解酶和动脉粥样硬化

• 批准号: 9006675
• 负责人: Zeneng Wang
• 金额: $ 43.39万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-22 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9006675
• 关键词: Adult; Animal Model; Animals; Atherosclerosis; Betaine; Blood; Cardiac; Cardiovascular Diseases; Carnitine; Cause of Death; Cholesterol; Choline; Cleaved cell; Clinical Research; Cloning; Complex; Dairy Products; Deposition; Development; Diet; Egg Yolk; Enzymes; Escherichia coli; Event; FMO3; Faculty; Fatty acid glycerol esters; Feces; Flavins; Foam Cells; Food; Funding; Future; Generations; Germ-Free; Goals; Hepatic; Human; Impairment; Individual; Knockout Mice; Laboratories; Lead; Lecithin; Link; Liver; Low Density Lipoprotein Receptor; Lyase; Manuscripts; Meat; Mediating; Metabolism; Metagenomics; Microbe; Mixed Function Oxygenases; Multienzyme Complexes; Mus; Myocardial Infarction; Nutrient; Nutritional; Oxidoreductase; Oxygenases; Pathway interactions; Peritoneal; Plasma; Plasmids; Play; Predisposition; Prevalence; Prevention; Recombinants; Reporting; Research; Research Personnel; Risk; Risk Factors; Role; Sampling; Source; Stroke; Substrate Specificity; Testing; Therapeutic; Vascular Diseases; Work; base; cardiovascular disorder risk; defined contribution; gut microbiota; in vivo; insight; macrophage; metabolomics; microbial; multidisciplinary; new therapeutic target; preference; professor; prospective; public health relevance; reverse cholesterol transport; saturated fat; small molecule; small molecule inhibitor; therapeutic target; trimethylamine; trimethyloxamine

 DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the leading cause of death in the world. Many risk factors have been identified as well as foods thought to be associated with increased CVD risks such as meats, high-fat dairy products, saturated fats and egg yolks. We described a previously unrecognized A meta-organismal pathway involving gut microbial (gut flora) dependent metabolism of trimethylamine-containing nutrients abundant in these foods (choline and l- carnitine) to trimethylamine (TMA) that is converted by the host liver enzymes to trimethylamine-N-oxide (TMAO) which is an atherogenic compound. We have shown using basic, animal model and human clinical studies that gut flora take part in development of CVD and its associated unfavorable events. Microbial enzymes responsible for generating TMA from various dietary TMA-containing nutrients are TMA lyases. Two microbial TMA lyases have been identified and cloned, CutC/D and CntA/B, which show strict substrate specificity for cleaving choline and carnitine, respectively. We recently cloned and characterized a related TMA lyase, YeaW/X, which demonstrates broad substrate specificity. In unpublished studies we see additional TMA lyase substrate activities in gut microbiota based on substrate preferences that are not catalyzed by either CutC/D or CntA/B. We propose to examine the relationship between specific microbial TMA lyases and the increased blood TMAO levels and development of atherosclerosis. We will further define the microbial TMA lyases responsible for TMA and TMAO generation in vivo, and the involvement of specific microbial TMA complexes (YeaW/X, CutC/D, and CntA/B) in diet-induced atherosclerosis using animal models. We will also test the potential of microbial choline TMA lyase complex pharmacologic manipulation in impacting host diet-induced impairment in reverse cholesterol transport and atherosclerosis. The proposed studies will help define the contribution that individual TMA lyase enzymes in vascular disease, and provide important nutritional and pharmacological insights into the prevention and treatment of atherosclerosis.

 描述（由适用提供）：心血管疾病（CVD）是世界上死亡的主要原因。已经确定了许多危险因素，以及被认为与CVD风险增加有关的食物，例如肉类，高脂乳制品，饱和脂肪和蛋黄。我们描述了一种先前未识别的元元途径，涉及肠道微生物（肠菌群）依赖的三甲胺的含有代谢，富含这些食物（胆碱和L-肉碱）富含三甲胺（TMA）的含三甲胺的养分（TMA）是由宿主liver liver liver liver liver liver liver liver liver liver insogen cologen in trimyteny-n-氧化物（TMO）转化为一位trimythy-n-氧化物。我们已经使用基本，动物模型和人类临床研究表明，肠道菌群参与了CVD的发展及其相关的不利事件。负责从各种含饮食TMA的营养物质产生TMA的微生物酶是TMA裂解酶。已经鉴定出和克隆了两个微生物TMA裂解酶，分别显示出严格的底物特异性，分别显示出严格的底物特异性。我们最近克隆并表征了相关的TMA裂解酶Yeaw/X，该裂解酶表现出广泛的底物特异性。在未发表的研究中，我们基于CUTC/D或CNTA/B催化的底物偏好，在肠道菌群中看到了其他TMA裂解酶底物活性。我们建议检查特定的微生物TMA裂解酶与血液TMAO水平的增加与动脉粥样硬化的发展之间的关系。我们将进一步定义导致体内TMA和TMAO产生的微生物TMA裂解酶，以及使用动物模型在饮食诱导的动脉粥样硬化中的特定微生物TMA复合物（YEAW/X，CUTC/D和CNTA/B）的参与。我们还将测试微生物胆碱裂解酶复合物药理操作的潜力，从而影响宿主饮食诱导的反向胆固醇转运和动脉粥样硬化的损伤。拟议的研究将有助于定义单个TMA裂解酶在血管疾病中的贡献，并为预防和治疗动脉粥样硬化提供重要的营养和药物见解。