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

• 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
• 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

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 残疾的原因。然而，针对 PAD 的药物疗法却很少。可可黄烷醇，来自可可种子 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 腓肠肌异常导致 PAD 残疾。我们最近资助的 COCOA PAD II 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。初步的 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 黄烷醇。首先，肠道微生物群将包括表儿茶素（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。代谢物发挥许多有益作用 影响。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， 一氧化氮的产生。其次，膳食补充剂可可黄烷醇可能促进肠道微生物分类群 与健康有关。因此，我们现在提出一项 COCOA PAD II 试验的辅助研究，该研究将 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。我们将具体测试以下内容 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 六分钟步行距离和六个月随访时腓肠肌灌注。其次，我们将确定 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） 月随访。第三，我们将确定可可黄烷醇是否会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 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 向上。如果我们的假设正确，这项试验将首次将肠道微生物组确定为 改善 PAD 患者步行表现的关键中介因素。结果还将描绘出 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。