Gut flora metabolism of dietary phosphatidylcholine and cardiovascular disease

描述（由申请人提供）：我们已经积累了新的数据，表明新的营养基础是动脉粥样硬化性心脏病发展的一个促成途径。总体途径涉及脂质饮食摄入（磷脂酰胆碱的胆碱部分）、肠道微生物群（肠道植物群）、遗传易感性（黄素单加氧酶3（FMO 3）的肝脏表达水平）之间的相互作用，以及促进动脉粥样硬化的代谢产物的产生。动脉粥样硬化性心脏病及其主要不良并发症（心肌梗死（MI）、中风和死亡）。肠道微生物群（“肠道植物群”）由数万亿典型的非致病性肠道生物组成，是我们最大的环境暴露--我们吃什么--的过滤器。肠道植物群发挥着重要作用，帮助消化和吸收许多营养物质。肠道植物群的改变可能与多种代谢途径的变化相关。同样，饮食的改变影响肠道植物群的组成和代谢产物的血浆水平。最近的动物研究表明，肠道微生物群落可以影响性状，对近交系小鼠品系的代谢组学研究表明，肠道微生物群可能在复杂代谢异常表型的发展中发挥积极作用，例如对胰岛素抵抗和非酒精性脂肪肝的易感性。肠道植物群依赖性磷脂代谢与动脉粥样硬化风险之间通过产生促动脉粥样硬化代谢物的联系尚未报道。本提案的总体目标是检验以下假设：膳食磷脂酰胆碱的肠道植物群依赖性代谢与心血管疾病的发病机制存在机械联系。具体目标是：目的1）验证膳食磷脂酰胆碱代谢物胆碱、TMANO和甜菜碱都是心脏病风险的诊断标志物并且与动脉粥样硬化的发展机制相关的假设。目的2）验证肠道植物群对动脉粥样硬化的调节作用。 公共卫生相关性：膳食磷脂酰胆碱的肠道菌群依赖性代谢与心血管疾病发病机制之间关系的发现为开发用于治疗和预防动脉粥样硬化性心脏病的新型诊断测试和治疗方法提供了机会。

DESCRIPTION (provided by applicant): We have accrued new data that suggests a new nutritional basis as a contributory pathway to the development of atherosclerotic heart disease. The overall pathway involves an interplay between dietary intake of lipid (the choline moiety of phosphatidyl choline), intestinal microbiota (gut flora), genetic susceptibility (hepatic expression levels of flavin monooxygenase 3, FMO3), and generation of pro-atherosclerotic metabolites that promote atherosclerotic heart disease and its major adverse complications (myocardial infarction (MI), stroke, and death). Intestinal microbiota ("gut flora"), comprised of trillions of typically non-pathogenic commensal organisms, serve as a filter for our greatest environmental exposure - what we eat. Gut flora play an essential role, aiding in the digestion and absorption of many nutrients. Alterations in gut flora can be associated with changes across a wide range of metabolic pathways. Similarly, alterations in diet influence both the composition of gut flora and plasma levels of metabolites. Animal studies have recently shown that intestinal microbial communities can influence traits, and metabolomic studies of inbred mouse strains have shown that gut microbiota may play an active role in the development of complex dysmetabolic phenotypes, such as susceptibility to insulin resistance and non-alcoholic fatty liver disease. Demonstration of a link between gut flora dependent phospholipid metabolism and atherosclerosis risk through generation of pro-atherosclerotic metabolites has not yet been reported. The overall goal of this proposal is to test the hypothesis that gut flora dependent metabolism of dietary phosphatidylcholine is mechanistically linked to the pathogenesis of cardiovascular disease. The specific aims are: Aim 1) Testing the hypothesis that dietary phosphatidylcholine metabolites choline, TMANO and betaine are both diagnostic markers for cardiac risk and mechanistically linked to development of atherosclerosis. Aim 2) Testing the hypothesis that gut flora plays a modulatory role in atherosclerosis. PUBLIC HEALTH RELEVANCE: Discovery of a relationship between gut flora-dependent metabolism of dietary phosphatidylcholine and cardiovascular disease pathogenesis provides opportunities for development of both novel diagnostic tests and therapeutic approaches for the treatment and prevention of atherosclerotic heart disease.