Microbial Trimethylamine Lyases and Atherosclerosis

 描述（由申请人提供）：心血管疾病（CVD）是世界上主要的死亡原因。许多危险因素已经被确定，以及被认为与心血管疾病风险增加有关的食物，如肉类，高脂肪乳制品，饱和脂肪和蛋黄。我们描述了一种以前未被认识到的A元生物途径，涉及肠道微生物（肠道植物群）依赖性代谢，将这些食物中丰富的含三甲胺的营养物质（胆碱和l-肉毒碱）代谢为三甲胺（TMA），所述三甲胺（TMA）被宿主肝酶转化为三甲胺-N-氧化物（TMAO），其是一种致动脉粥样硬化化合物。我们已经使用基础、动物模型和人类临床研究表明，肠道植物群参与CVD及其相关不利事件的发展。负责从各种含TMA的膳食营养素产生TMA的微生物酶是TMA裂解酶。已经鉴定并克隆了两种微生物TMA裂解酶，CutC/D和CntA/B，它们分别显示出对胆碱和肉毒碱的裂解的严格底物特异性。我们最近克隆并表征了一个相关的TMA裂解酶，YeaW/X，它表现出广泛的底物特异性。在未发表的研究中，我们看到了基于底物偏好的肠道微生物群中额外的TMA裂解酶底物活性，其不被CutC/D或CntA/B催化。我们建议研究特定微生物TMA裂解酶与血液TMAO水平升高和动脉粥样硬化发展之间的关系。我们将使用动物模型进一步确定负责体内TMA和TMAO生成的微生物TMA裂解酶，以及特定微生物TMA复合物（YeaW/X、CutC/D和CntA/B）在饮食诱导的动脉粥样硬化中的参与。我们还将测试微生物胆碱TMA裂解酶复合物药理学操作在影响宿主饮食诱导的胆固醇逆向转运和动脉粥样硬化损伤中的潜力。拟议的研究将有助于确定单个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理学见解。

 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 In unpublished studies we see additional TMA lyase substrate activities in gut microbiota based on substrate preferences that are not catalyzed by either CutC/D or CntA/B. We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.