Gut flora metabolism of dietary phosphatidylcholine and cardiovascular disease

描述(申请人提供)：我们积累了新的数据，表明一种新的营养基础是动脉粥样硬化性心脏病发展的一个贡献途径。整个途径涉及饮食摄入脂质(磷脂酰胆碱的胆碱部分)、肠道微生物区系(肠道菌群)、遗传易感性(肝脏黄素单加氧酶3的表达水平)以及促进动脉粥样硬化性心脏病及其主要不良并发症(心肌梗死、中风和死亡)的前动脉粥样硬化代谢物的产生之间的相互作用。肠道微生物区系(“肠道菌群”)由数万亿个典型的非致病共生生物组成，是我们最大的环境暴露--我们吃什么--的过滤器。肠道菌群起着至关重要的作用，有助于消化和吸收许多营养物质。肠道菌群的变化可能与多种代谢途径的变化有关。同样，饮食的改变会影响肠道菌群的组成和血浆代谢物的水平。最近的动物研究表明，肠道微生物群落可以影响性状，对近交系小鼠的代谢组学研究表明，肠道微生物区系可能在复杂代谢异常表型的发展中发挥积极作用，如对胰岛素抵抗和非酒精性脂肪性肝病的易感性。有关肠道菌群依赖的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之间的联系的研究尚未见报道。这项建议的总体目标是检验这一假设，即饮食中磷脂酰胆碱的肠道菌群依赖的代谢与心血管疾病的发病机制有关。其具体目的是：1)验证饮食中磷脂酰胆碱代谢产物胆碱、TMANO和甜菜碱都是心脏风险的诊断标记物，并与动脉粥样硬化的发生有机械联系的假设。目的2)验证肠道菌群在动脉粥样硬化中起调节作用的假说。 公共卫生相关性：膳食磷脂酰胆碱依赖肠道菌群代谢与心血管疾病发病机制之间的关系的发现，为开发治疗和预防动脉粥样硬化性心脏病的新的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.