Gut flora metabolism of dietary phosphatidylcholine and cardiovascular disease

膳食磷脂酰胆碱的肠道菌群代谢与心血管疾病

• 批准号: 8460968
• 负责人: Stanley L Hazen
• 金额: $ 68.88万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8460968
• 关键词: Amines; Animal Model; Animals; Antibiotics; Apolipoprotein E; Atherosclerosis; Betaine; Biology; CD36 gene; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cessation of life; Chemicals; Cholesterol; Choline; Clinical; Clinical Trials; Complex; Data; Development; Diagnostic; Diagnostic tests; Diet; Dietary Fats; Dietary Supplementation; Dietary intake; Digestion; Disease; Eating; Environmental Exposure; Etiology; Event; Fasting; Fishes; Flavins; Foam Cells; Generations; Genetic; Genetic Predisposition to Disease; Genetic Variation; Germ-Free; Goals; Heart Diseases; Hepatic; Hereditary Disease; High Density Lipoprotein Cholesterol; Human; Human Genetics; Inbred Strains Mice; Individual; Inflammatory; Insulin Resistance; Intestines; Knockout Mice; Learning; Lecithin; Link; Lipids; Liver diseases; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mixed Function Oxygenases; Monitor; Morbidity - disease rate; Mus; Mutation; Myocardial Infarction; Names; Nutrient; Nutritional; Odors; Organism; Pathogenesis; Pathway interactions; Performance; Phenotype; Phospholipid Metabolism; Plasma; Play; Predisposition; Prevention; Probiotics; Process; Production; Reporting; Risk; Role; Stroke; Syndrome; Testing; Therapeutic; Ultrasonography; Up-Regulation; Validation; absorption; base; cohort; gut microbiota; liquid chromatography mass spectrometry; macrophage; macrophage scavenger receptors; metabolomics; microbial; microbial community; mouse model; non-alcoholic fatty liver; novel diagnostics; prognostic; public health relevance; receptor expression; reverse cholesterol transport; scavenger receptor; small molecule; trait; trimethyloxamine

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.

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（磷脂酰胆碱的胆碱部分）的饮食摄入、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）和促动脉粥样硬化代谢产物（其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（MI）、中风和死亡））的产生之间的相互作用。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。动物研究最近表明，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疾病的易感性。尚未报道肠道植物群依赖性磷脂代谢与通过产生促动脉粥样硬化代谢物而导致的动脉粥样硬化风险之间的联系。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。