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: 10410651
• 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/10410651
• 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; Diet Monitoring; 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; Oxides; 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; base; 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.

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