# COCOA PAD II Trial: Microbiome Ancillary Study

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2022 · $182,955

## Abstract

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 therapeuti...

## Key facts

- **NIH application ID:** 10610072
- **Project number:** 3R01AG068458-02S1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Mary McGrae McDermott
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $182,955
- **Award type:** 3
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10610072

## Citation

> US National Institutes of Health, RePORTER application 10610072, COCOA PAD II Trial: Microbiome Ancillary Study (3R01AG068458-02S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10610072. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*