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

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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.