Microbial Trimethylamine Lyases and Atherosclerosis

 描述(申请人提供)：心血管疾病(CVD)是世界上最主要的死亡原因。已经确定了许多风险因素，以及被认为与心血管疾病风险增加有关的食品，如肉类、高脂肪乳制品、饱和脂肪和蛋黄。我们描述了一种先前未知的代谢生物途径，涉及肠道微生物(肠道菌群)依赖于这些食物中丰富的含有三甲胺的营养物质(胆碱和L肉碱)代谢成三甲胺，三甲胺被宿主肝脏酶转化为三甲胺-N-氧化物(TMAO)，三甲胺-N-氧化物是一种致动脉粥样硬化化合物。我们已经通过基础、动物模型和人类临床研究表明，肠道菌群参与了CVD及其相关不良事件的发生发展。负责从各种饮食中含有TMA的营养素中产生TMA的微生物酶是TMA裂解酶。已鉴定和克隆了两种微生物TMA裂解酶，CutC/D和CNTA/B，它们分别对分解胆碱和肉碱具有严格的底物专一性。我们最近克隆并鉴定了一个相关的TMA裂解酶YeaW/X，它具有广泛的底物特异性。在未发表的研究中，我们看到肠道微生物区系中额外的TMA裂解酶底物活性是基于底物偏好，而这些底物不是由CutC/D或CNTA/B催化的。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的关系。我们将通过动物模型进一步确定在体内产生TMA和TMAO的微生物TMA裂解酶，以及特定的微生物TMA复合体(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裂解酶复合体药物操作在影响宿主饮食诱导的胆固醇反向运输和动脉粥样硬化方面的潜力。拟议的研究将有助于确定单个TMA裂解酶在血管疾病中的作用，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 In unpublished studies we see additional TMA lyase substrate activities in gut microbiota based on substrate preferences that are not catalyzed by either CutC/D or CntA/B. We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.