Genes and Nutrition: Dietary Choline, the Gut Microbiota, and Atrial Fibrillation

基因与营养：膳食胆碱、肠道微生物群和心房颤动

• 批准号: 10646383
• 负责人: Robert Alden Koeth
• 金额: $ 40.25万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646383
• 关键词: Ablation; Action Potentials; Acute; Adipose tissue; Alcohol abuse; Animal Model; Anti-Arrhythmia Agents; Antibiotics; Anticoagulants; Anticoagulation; Atherosclerosis; Atrial Fibrillation; Blood Platelets; Cardiac Myocytes; Cardiovascular system; Catabolism; Catheters; Cheese; Choline; Chronic; Data; Diet; Doctor of Philosophy; Electrophysiology (science); Endothelium; Enzymes; Epidemiology; Event; Fibroblasts; Fibrosis; Flavins; Functional disorder; Genes; Heart; Heart Atrium; Heart failure; Human; Hyperactivity; In Vitro; Inflammasome; Inflammation; Inflammatory; Intervention; Ischemic Stroke; Left; Link; Liver; Longitudinal cohort; Maps; Meat; Membrane Potentials; Metabolic; Metabolism; Mitochondria; Mixed Function Oxygenases; Monitor; Morbidity - disease rate; Mus; Muscle Cells; Obesity; Optics; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Plasma; Predisposition; Procedures; Production; Reactive Oxygen Species; Reporting; Research Personnel; Risk; Risk Factors; Role; Source; Stroke; Thrombosis; acquired factor; cardiac tissue engineering; dietary; egg; experimental study; fecal transplantation; genome wide association study; gut microbiome; gut microbiota; induced pluripotent stem cell; induced pluripotent stem cell derived cardiomyocytes; inhibitor; insight; marenostrin; microbiome; microbiota transplantation; mortality; mouse model; novel; nutrition; prevent; stroke risk; tool; trait; trimethylamine; trimethyloxamine

Summary: Atrial fibrillation (AF) is multifactorial and acquired factors, such as obesity, alcohol abuse, and heart failure, contribute to its pathogenesis. Moreover, despite the use of anticoagulants to prevent left atrial thrombosis, patients with AF are still at risk for ischemic stroke or the complications of anticoagulation. Our inability to manage AF with available tools emphasizes the critical need to search for novel treatment pathways that target its underlying mechanisms. Over the past several years the gut microbiome has been linked to atherosclerotic disease by gut microbiota catabolism of dietary choline to trimethylamine (TMA) which is further oxidized in the liver by flavin monooxygenase to trimethylamine N-oxide (TMAO). Elevated plasma TMAO levels independently predict major adverse cardiovascular events (MACE) and have been mechanistically linked to atherosclerotic disease by (i) increasing endothelial inflammation by priming and activating the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome by the production of mitochondrial reactive oxygen species, (ii) increasing adiposity by regulating white adipose tissue, and (iii) enhancing thrombosis by activating platelets. The NLRP3 inflammasome has been linked to the pathogenesis of AF in animal models, obesity is a major risk factor for AF, and enhancement of thrombosis by TMAO may increase AF patients’ susceptibility to stroke. We have gathered preliminary data demonstrating that (i)TMAO independently associates with prevalent and incident AF, (ii)TMAO may prime the NLRP3 inflammasome in atrial-like induced pluripotent stem cell-derived cardiomyocytes (a-iCMs), (iii) TMAO blunts the atrial action potential in ex vivo mouse hearts in a gut microbiota dependent manner, and (iv) TMAO reduces the resting potential and shortens the duration and decreases the peak amplitude of the action potential in a-iCMS. These data suggest TMAO may be involved in the pathogenesis of AF by causing metabolic and electrophysiological dysfunction in cardiomyocytes, thereby promoting AF. In this project, we propose to investigate the mechanisms underlying the association of TMAO and the gut microbiome with AF. Aim 1 will investigate the role of the gut microbiome in AF susceptibility. We will first suppress the entire gut microbiota with broad spectrum antibiotics using AF susceptible mice on and off a choline diet and monitor for the progression of AF. We then will use a pathway specific inhibitor, fluoromethylcholine (FMC), to demonstrate that choline metabolism to TMAO is specifically promoting AF. In a final set of studies, we will confirm the role of the gut microbiota in AF by performing fecal transplants to determine if susceptibility to AF is a transmissible trait. The second aim will investigate mechanisms by which TMAO promote AF. The first subaim will explore the role of the NLRP3 inflammasome in the TMAO-promoted susceptibility to AF, fibrosis, and left atrial thrombosis. The second sub aim will explore the role of TMAO in causing electrophysiological dysfunction in ex vivo mouse atrial studies and in atrial engineered heart tissue. Together these studies may link together the diet, the gut microbiome, and AF.

总结： 心房颤动（AF）是多因素和后天因素，如肥胖、酗酒和心力衰竭， 有助于其发病机制。此外，尽管使用抗凝剂来预防左心房血栓形成， AF患者仍有缺血性卒中或抗凝并发症的风险。我们无法 使用现有工具管理AF强调了寻找新的治疗途径的迫切需要， 其潜在机制。在过去的几年里，肠道微生物组与动脉粥样硬化有关。 肠道微生物群将饮食中的胆碱转化为三甲胺（TMA）， 肝脏通过黄素单加氧酶转化为三甲胺N-氧化物（TMAO）。血浆TMAO水平升高 独立预测主要不良心血管事件（MACE），并与 （i）通过引发和激活NOD-，LRR-， 和含pyrin结构域3（NLRP 3）炎性体通过线粒体活性氧的产生 物种，（ii）通过调节白色脂肪组织增加肥胖，和（iii）通过调节 激活血小板在动物模型中，NLRP 3炎性体与AF的发病机制有关， 肥胖是房颤的主要危险因素，TMAO增强血栓形成可能会增加房颤患者的 中风易感性。我们已经收集了初步数据，表明（i）TMAO独立 与普遍的和偶发的AF相关，（ii）TMAO可能在心房样诱导的房颤中引发NLRP 3炎性小体。 多能干细胞衍生的心肌细胞（a-iCM），（iii）TMAO钝化离体心房动作电位 小鼠心脏以肠道微生物群依赖的方式，和（iv）TMAO降低静息电位， 缩短了a-iCMS中动作电位的持续时间并降低了动作电位的峰值幅度。这些数据表明 TMAO可能通过引起房颤患者的代谢和电生理功能障碍参与房颤的发病机制。 在这个项目中，我们建议调查的机制， TMAO和肠道微生物组与AF的关联。Aim 1将研究肠道微生物组的作用 房颤的易感性。我们将首先使用AF用广谱抗生素抑制整个肠道微生物群 易感小鼠和关闭胆碱饮食和监测AF的进展。然后，我们将使用一种途径， 特异性抑制剂，氟甲基胆碱（FMC），以证明胆碱代谢为TMAO是特异性 促进AF。在最后一组研究中，我们将通过进行粪便试验来证实肠道微生物群在AF中的作用。 移植以确定对AF的易感性是否是一种可传播的性状。第二个目标将调查 第一个子目标将探索NLRP 3炎性小体在TMAO促进AF中的作用。 TMAO促进了对AF、纤维化和左心房血栓形成的易感性。第二个子目标将探索 TMAO在离体小鼠心房研究中引起电生理功能障碍中的作用以及在心房肌中的作用 工程心脏组织。这些研究可能将饮食，肠道微生物组和AF联系在一起。