COCOA PAD II: Effect of Cocoa Flavanols on the Gut Microbiome and Functional Performance

COCOA PAD II：可可黄烷醇对肠道微生物组和功能表现的影响

基本信息

批准号：
10811104
负责人：
KAREN J. HO
金额：
$ 48.66万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-30 至 2025-09-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10811104
关键词：
Administrative Supplement Adult Affect Ancillary Study Animal Model Atherosclerosis Bifidobacterium Biological Biopsy Blood Blood specimen Butyrates Cacao Plant Cessation of life Characteristics Circulation Clinical Trials Cocoa Powder Development Dietary Supplementation Double-Blind Method Elderly Endothelium Enrollment Eubacterium Feces Flavanol Funding Future Gastrocnemius Muscle Health Human Volunteers Impairment In Vitro Inflammation Infrastructure Intervention Ischemia Lactobacillus Lower Extremity Measures Mediating Mediator Medical Microbe Mitochondria Muscle Myocardial Infarction NOS3 gene Nitric Oxide Obstruction Organ Outcome Outcome Study Parents Participant Pathway interactions Patients Performance Perfusion Peripheral arterial disease Persons Phosphorylation Physical activity Pilot Projects Placebos Plasma Probiotics Production Property Resources Role Sampling Schedule Skeletal Muscle Stroke Testing Therapeutic Time Trees Volatile Fatty Acids Walking brachial artery disability endothelial dysfunction endurance exercise epicatechin follow-up functional decline gut microbiome gut microbiota improved metabolome metabolomics meter microbial microbiota participant enrollment preclinical study prevent primary outcome randomized trial randomized, clinical trials response secondary outcome stool sample therapeutic target

项目摘要

ABSTRACT Lower extremity peripheral artery disease (PAD) affects more than 230 million people worldwide and is a major cause of disability. Yet few medical therapies exist for PAD. Cocoa flavanols, from the seeds of theobroma cacao, the “cocoa” tree, have therapeutic properties that may improve calf muscle perfusion and reverse the gastrocnemius muscle abnormalities that contribute to disability in PAD. Our recently funded COCOA PAD II Trial (R01-AG068458) is a multi-center double-blinded randomized trial that will test the effects of cocoa flavanols vs. placebo on change in six-minute walk distance at six month follow-up in people with PAD. Secondary outcomes include gastrocnemius perfusion, physical activity, brachial artery flow-mediated dilation and gastrocnemius muscle biopsy measures of mitochondrial activity and skeletal muscle health. Preliminary evidence supports our hypothesis that gut microbiota may be key mediators of the beneficial effects of cocoa flavanols. First, gut microbiota metabolize cocoa flavanols including epicatechin (the main cocoa flavanol) to produce metabolites that enter the circulation and reach target organs. The metabolites exert many beneficial effects. Microbe-derived flavanol metabolites increase phosphorylation of endothelial nitric oxide synthase and nitric oxide production. Second, dietary supplementation of cocoa flavanols may promote gut microbial taxa associated with health. Therefore, we now propose an ancillary study to the COCOA PAD II Trial that will enable us to collect and analyze stool and plasma samples collected at baseline and six month follow-up from 100 participants with PAD who will be enrolled in the COCOA PAD II Trial. We will test the following specific aims: First, among people with PAD, we will determine whether baseline gut microbial diversity and composition are associated with the degree of response to cocoa flavanols, measured by greater improvement in six-minute walk distance and gastrocnemius perfusion at 6-month follow-up. Second, we will determine whether cocoa flavanols, compared to placebo, favorably alter gut microbial diversity and composition at six- month follow-up. Third, we will determine whether cocoa flavanol-induced changes in gut microbial composition, compared to placebo, between baseline and 6-month follow-up are associated with greater improvement in six-minute walk distance and gastrocnemius perfusion. Finally, we will perform microbe- associated metabolomic profiling of blood samples at six-month follow-up to identify metabolomic profiles that are associated with improved six-minute walk distance and gastrocnemius muscle perfusion at 6-month follow- up. If our hypotheses are correct, this trial will, for the first time, establish the gut microbiome as a critical mediator of improved walking performance in people with PAD. Results will also delineate a key biologic pathway of improved walking performance in PAD, thereby identifying the gut microbiome a therapeutic target for future interventions in PAD.

抽象的下肢外周动脉疾病 (PAD) 影响着全球超过 2.3 亿人，是一种主要的疾病然而，来自可可种子的可可黄烷醇却很少有治疗方法。可可，即“可可”树，具有治疗特性，可以改善小腿肌肉灌注并逆转我们最近资助的 COCOA PAD II 导致腓肠肌异常。试验（R01-AG068458）是一项多中心双盲随机试验，将测试可可的效果黄烷醇与安慰剂对 PAD 患者六个月随访时六分钟步行距离变化的影响。次要结果包括腓肠肌灌注、体力活动、肱动脉血流介导的扩张和腓肠肌活检测量线粒体活性和骨骼肌健康状况。证据支持我们的假设，即肠道微生物群可能是可可有益作用的关键介质首先，肠道微生物将包括表儿茶素（主要可可黄烷醇）在内的可可黄烷醇代谢为产生进入循环并到达靶器官的代谢物，这些代谢物发挥许多有益作用。微生物衍生的黄烷醇代谢物增加内皮一氧化氮合酶的磷酸化和其次，膳食补充可可黄烷醇可能会促进肠道微生物分类群的产生。因此，我们现在提出一项 COCOA PAD II 试验的辅助研究。使我们能够收集和分析基线和六个月随访时收集的粪便和血浆样本 100 名患有 PAD 的参与者将参加 COCOA PAD II 试验，我们将测试以下具体内容。目标：首先，在 PAD 患者中，我们将确定基线肠道微生物多样性和成分与对可可黄烷醇的反应程度相关，通过更大的改善来衡量其次，我们将确定 6 分钟步行距离和 6 个月随访时的腓肠肌灌注。与安慰剂相比，可可黄烷醇是否能有利地改变肠道微生物的多样性和组成（六）第三，我们将确定可可黄烷醇是否引起肠道微生物的变化。与安慰剂相比，基线和 6 个月随访之间的成分与更大的相关性六分钟步行距离和腓肠肌灌注的改善最后，我们将进行微生物检查。在六个月的随访中对血液样本进行相关代谢组学分析，以确定代谢组学概况与 6 个月随访时六分钟步行距离和腓肠肌灌注的改善相关如果我们的假设是正确的，这项试验将首次将肠道微生物组确定为一个模型。 PAD 患者步行表现改善的关键中介因素结果还将描述一个因素。改善 PAD 步行性能的关键生物学途径，从而识别肠道微生物组未来 PAD 干预的治疗目标。