COCOA PAD II Trial: Microbiome Ancillary Study

COCOA PAD II 试验：微生物组辅助研究

• 批准号: 10610072
• 负责人: Mary McGrae McDermott
• 金额: $ 18.3万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10610072
• 关键词: Administrative Supplement; Affect; Aging; Ancillary Study; Applications Grants; Arteries; Bifidobacterium; Biological; Biopsy; Blood Circulation; Cacao Plant; Characteristics; Chicago; Clinical Trials; Clostridium; Cocoa Powder; Collection; Data Collection; Double-Blind Method; Elderly; Enrollment; Exercise; Feces; Flavanol; Funding; Future; Gastrocnemius Muscle; Health; Human; Human Microbiome; Infrastructure; Intervention; Ischemia; Laboratories; Lactobacillus; Lower Extremity; Measures; Mediating; Mediator of activation protein; Medical; Microbe; Mitochondria; Muscle; Muscle function; Obstruction; Organ; Outcome; Outcome Study; Oxidative Stress; Participant; Pathway interactions; Performance; Perfusion; Peripheral; Peripheral arterial disease; Persons; Physical activity; Placebos; Plasma; Preparation; Property; Randomized; Sampling; Seeds; Skeletal Muscle; Specimen; Testing; Therapeutic; Time; Tissues; Trees; Walking; Work; brachial artery; disability; epicatechin; follow-up; gut microbes; gut microbiome; gut microbiota; improved; improved outcome; metabolomics; meter; microbial; microbiome; pilot trial; randomized trial; response; secondary outcome; stool sample; therapeutic target

ABSTRACT Cocoa flavanols, from the seeds of theobroma cacao, the “cocoa” tree, have therapeutic properties that may improve lower extremity perfusion and reverse gastrocnemius muscle abnormalities that contribute to disability in people with lower extremity peripheral artery disease (PAD). Our 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 mediate the beneficial effects of cocoa flavanols. First, gut microbiota metabolize cocoa flavanols to produce metabolites that enter the circulation and reach target organs where these metabolites may exert beneficial effects. Second, cocoa flavanols increase abundance of Bifidobacteria and Lactobacillus spp. but decrease Clostridium spp. in the gut microbiome. These microbiome changes have been associated with improved muscle function and exercise ability as well as reduced oxidative stress. Therefore, we request an Administrative Supplement (PA 20-227) for a 12 month period to support collection of stool and plasma samples and preparation of samples for analyses. Collected samples will be sent to Dr. Eric Pamer’s laboratory at the U. of Chicago for analyses. During this one year of funding, we anticipating collecting samples from approximately 50 participants at baseline and approximately 40 participants at six-month follow-up who are participants in the COCOA PAD II Trial. We will test the following specific aims: First, among people with PAD, we will assess whether cocoa flavanols, compared to placebo, favorably alter gut bacterial diversity, composition, and gut-microbe associated metabolomics at six-month follow-up. Second, among people with PAD randomized to cocoa flavanols, we will assess whether more favorable changes in gut bacterial diversity, composition, and gut microbe related metabolites between baseline and 6-month follow-up are associated with greater improvement in six-minute walk and other study outcomes at 6-month follow-up. Third, among people with PAD randomized to cocoa flavanols, we will assess whether baseline characteristics of the gut microbiome are associated with the degree of response to cocoa flavanols, measured by greater improvement in six-minute walk distance and other outcomes 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 the effects of cocoa flavanols on improved walking performance in humans. Results will also delineate a key biologic pathway of cocoa flavanol therapy, and identify the gut microbiome as an important therapeutic target for future interventions.

摘要 来自可可树可可种子的可可黄烷醇具有治疗特性， 可以改善下肢灌注和逆转腓肠肌异常， 下肢外周动脉疾病（PAD）患者的残疾。我们资助的可可PAD II试验 （R 01-AG 068458）是一项多中心双盲随机试验，将测试可可黄烷醇的作用 vs.安慰剂对PAD患者6个月随访时6分钟步行距离的变化。二次 结果包括腓肠肌灌注，体力活动，肱动脉血流介导的扩张， 腓肠肌活检测量线粒体活性和骨骼肌健康。 初步证据支持我们的假设，即肠道微生物群可能介导 可可黄烷醇首先，肠道微生物群代谢可可黄烷醇以产生进入胃肠道的代谢物。 循环并到达这些代谢物可能发挥有益作用的靶器官。二、可可 黄烷醇增加双歧杆菌和乳杆菌属的丰度。但减少梭菌属。肠道中 微生物组这些微生物群的变化与改善肌肉功能和锻炼有关 能力以及减少氧化应激。因此，我们要求行政补充（PA 20-227） 为期12个月，以支持粪便和血浆样本的采集以及样本的制备， 分析。收集的样本将被送往埃里克·帕默博士在美国的实验室。芝加哥分析。 在这一年的资助期间，我们预计将从大约50名参与者中收集样本， 基线时，约40名参与者在6个月随访时参加了可可PAD II 审判我们将测试以下具体目标：首先，在PAD患者中，我们将评估可可是否 与安慰剂相比，黄烷醇有利地改变肠道细菌多样性、组成和肠道微生物相关性 6个月随访时的代谢组学。其次，在随机接受可可黄烷醇治疗的PAD患者中， 评估肠道细菌多样性、组成和肠道微生物相关的更有利的变化是否 基线和6个月随访之间的代谢产物与6分钟内的更大改善相关。 6个月随访时的步行和其他研究结局。第三，在随机接受可可的PAD患者中， 黄烷醇，我们将评估肠道微生物组的基线特征是否与 对可可黄烷醇的反应程度，通过6分钟步行距离的更大改善来衡量， 6个月随访时的其他结局。如果我们的假设是正确的，这场审判将首次， 建立肠道微生物组作为可可黄烷醇对改善 人类的行走能力。结果还将描绘可可黄烷醇的一个重要生物学途径 治疗，并确定肠道微生物组作为未来干预的重要治疗靶点。