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).

项目概要 在过去的十年中，人们越来越认识到肠道微生物群与 许多心血管表型。最突出的之一是肠道微生物代谢之间的联系 来自膳食来源（胆碱、磷脂酰胆碱、左旋肉碱等）和 CVD 的三甲胺 (TMA) 部分。肠道 微生物通过 cutC TMA 裂解酶的作用代谢膳食胆碱以释放 TMA。 TMA被吸收，然后 被肝黄素单加氧酶（FMO3）氧化形成三甲胺N-氧化物（TMAO）。三甲胺TMAO已 在动物模型中与动脉粥样硬化血栓性疾病存在因果关系，并且在队列研究中可预测 CVD 风险。这 该 R21 提案的总体目标是： 1) 确定可行性并建立效果的概念验证 补充酒石酸氢胆碱对中年成人循环TMAO和内皮依赖性扩张的影响 以便将来进行更大规模、更全面的试验； 2）建立我们测量肠道的能力 微生物群的组成和功能； 3) 获得效应量生成的初步数据。为此，遵循 在为期两周的引导饮食中，我们将随机分配 24 名中年成年人（45-65 岁）接受为期 4 周的酒石酸氢胆碱 （1000 毫克/天）或安慰剂。受试者的所有食物中胆碱和 TMA 部分的摄入量均维持在 研究期间美国饮食的膳食水平从我们的代谢厨房摄入，以避免潜在的混淆 通过个人之间习惯性饮食摄入TMA部分的差异。 TMAO 的测量 通过 UPLC-MS/MS 进行浓缩，使用高分辨率超声进行流介导扩张，以及肠道微生物群 分别使用 16S rRNA 焦磷酸测序和靶向 qt-PCR 进行成分/功能分析 每 4 周治疗期后。这项创新的综合和转化生理学研究将 由一位既定的 P.I. 进行和具有丰富经验和良好成功记录的调查团队 进行针对心脏代谢功能障碍的干预研究。这些研究具有重要的转化意义 潜力，因为它们可以将啮齿类动物的基础科学发现推广到人类，并提供新的机制见解 通过确定膳食胆碱对内皮功能的影响，对人类进行了观察性研究 与宿主肠道微生物群的相互作用。反过来，肠道微生物群可能是治疗的关键目标 有助于维持健康的内皮或治疗内皮功能障碍。重要的是，我们的研究 还将提供对肠道微生物群的深入了解，肠道微生物群是个体间变异增加的重要来源 TMAO 和血流介导的扩张对膳食胆碱摄入的反应。因此，后者可能提供理由 针对肠道微生物群作为我们所吃食物之间的界面的个性化营养或其他干预措施 和宿主生理学（即内皮功能）。