Gut Microbiota, Trimethylamine N-Oxide, and Endothelial Dysfunction in Middle-Aged Adults

中年成人肠道微生物群、氧化三甲胺和内皮功能障碍

• 批准号: 9789801
• 负责人: KEVIN P DAVY
• 金额: $ 23.65万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789801
• 关键词: Adult; Adverse effects; Age; Animal Model; Ascorbic Acid; Bacteria; Basic Science; Blood Circulation; Blood Vessels; Carbohydrates; Cardiovascular system; Choline; Cleaved cell; Cohort Studies; Data; Diet; Dietary intake; Disease; Eating; Elderly; Endothelium; Enzymes; Event; FMO3; Fatty acid glycerol esters; Flavins; Food; Functional disorder; Future; Generations; Hepatic; Human; Impairment; Individual; Individual Differences; Infusion procedures; Intake; Intervention; Intervention Studies; Lead; Lecithin; Levocarnitine; Link; Liver; Lyase; Maintenance; Measurement; Measures; Mediating; Metabolic; Metabolism; Micronutrients; Mixed Function Oxygenases; Nutritional; Observational Study; Oxidative Stress; Oxides; Phenotype; Physiological; Physiology; Placebos; Plasma; Proteins; Randomized; Resolution; Ribosomal RNA; Risk; Risk Factors; Rodent; Rodent Model; Source; Supplementation; Ultrasonography; cardiometabolism; cardiovascular disorder risk; delta opioid receptor; endothelial dysfunction; experience; gut bacteria; gut microbes; gut microbiota; indexing; innovation; insight; inter-individual variation; microbial; middle age; novel; pyrosequencing; response; success; targeted treatment; treatment duration; trimethylamine; trimethyloxamine; vascular inflammation

Project Summary In the past decade, there has been increasing appreciation for an association between the gut microbiota and numerous cardiovascular phenotypes. One of the most prominent has been the link between gut microbial metabolism of trimethylamine (TMA) moieties from dietary sources (choline, phosphatidylcholine, L-carnitine, etc.) and CVD. Gut microbes metabolize dietary choline to release TMA via the action of cutC TMA lyase. TMA is absorbed and then oxidized by hepatic flavin monooxygenases (FMO3) to form trimethylamine N-oxide (TMAO). TMAO has been causally linked to atherothrombotic disease in animal models and is predictive of CVD risk in cohort studies. The overall objectives of this R21 proposal are to: 1) determine the feasibility and establish proof-of-concept for the effects of choline bitartrate supplementation on circulating TMAO and endothelial-dependent dilation in middle-aged adults in order to conduct a larger, more comprehensive trial in the future; 2) establish our proficiency in measuring gut microbiota composition and function; and 3) obtain preliminary data for effect size generation. To this end, following a two-week lead-in diet, we will randomize twenty-four middle-aged adults (45-65 yrs) to 4-weeks of choline bitartrate (1000 mg/d) or placebo. Subjects will be provided all of their food with choline and TMA-moiety intake maintained at meal levels intake of the US diet for the duration of the study from our metabolic kitchen to avoid potential confounding through differences in habitual dietary intake of TMA moieties between individuals. Measurements of TMAO concentration by UPLC-MS/MS, flow-mediated dilation using high resolution ultrasound, and gut microbiota composition/function using 16S rRNA pyrosequencing and targeted qt-PCR, respectively will be made before and following each 4-week treatment period. This innovative integrative and translational physiological study will be conducted by an established P.I. and investigative team with extensive experience and a strong record of success performing intervention studies targeting cardiometabolic dysfunction. These studies have significant translational potential as they may advance basic science findings in rodents to humans and provide novel mechanistic insight into observational studies in humans by establishing the effect of dietary choline on endothelial function through its interaction with the host intestinal microbiota. In turn, the gut microbiota may be a key target for therapies that may contribute to the maintenance of a healthy endothelium or treatment of endothelial dysfunction. Importantly, our study also will provide insight into the gut microbiota as important source of inter-individual variability in the increase in TMAO and flow-mediated dilation responses to dietary choline intake. As such, the latter may provide rationale for individualizing nutritional or other interventions that target the gut microbiota as an interface between the food we eat and host physiology (i.e., endothelial function).

项目摘要 在过去的十年中，人们对肠道微生物群和 许多心血管表型。最突出的是肠道微生物代谢之间的联系 来自饮食来源（胆碱，磷脂酰胆碱，L-肉碱等）和CVD的三甲胺（TMA）部分。肠 微生物通过CUTC TMA裂解酶的作用代谢饮食胆碱释放TMA。 TMA被吸收，然后 用肝黄素单加氧酶（FMO3）氧化以形成三甲胺N-氧化物（TMAO）。 tmao曾经 与动物模型中的动脉瘤性疾病有因果关系，并可以预测队列研究中的CVD风险。这 该R21提案的总体目标是：1）确定可行性并确定效果的概念证明 在中年成年人中循环TMAO和内皮依赖性扩张上补充了胆碱的比特酸盐补充剂 为了将来进行更大，更全面的试验； 2）确定我们测量肠道的熟练程度 微生物群的组成和功能； 3）获取效果尺寸产生的初步数据。为此，遵循 我们将为两周的饮食饮食，我们将二十四个中年成年人（45 - 65年）随机地到4周 （1000 mg/d）或安慰剂。将向受试者提供所有食物，并保持胆碱和TMA运动的摄入量 在我们的代谢厨房的研究期间，美国饮食的进餐水平摄入量 通过习惯性饮食摄入个体之间的TMA部分饮食摄入量的差异。 TMAO的测量 通过高分辨率超声和肠道微生物群，通过UPLC-MS/MS的浓度，流量介导的扩张 使用16S rRNA pyrosequencing和靶向QT-PCR的组成/功能将分别制作和 每个4周的治疗期之后。这项创新的综合和转化生理研究将是 由已建立的P.I.进行和具有丰富经验和成功记录的调查团队 靶向心脏代谢功能障碍的干预研究。这些研究具有重大的翻译 潜在的潜力可能会推进啮齿动物的基本科学发现，并为人类提供新颖的机械洞察力 通过建立饮食胆碱对内皮功能的影响，通过其观察性研究 与宿主肠菌群的相互作用。反过 有助于维持健康的内皮或内皮功能障碍的治疗。重要的是，我们的研究 还将洞悉肠道菌群，是个体间变异性的重要来源 TMAO和流动介导的扩张对饮食胆碱摄入的反应。因此，后者可以为 个性化营养或其他针对肠道微生物群的干预措施，作为我们吃的食物之间的接口 和宿主生理（即内皮功能）。