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Purpose: Trimethylamine-N-oxide (TMAO) is a gut-derived metabolite associated with cardiovascular disease (CVD). In preclinical and observational studies, resveratrol and exercise training have been suggested as potential strategies to reduce the systemic levels of TMAO. However, evidence from experimental studies in humans remains unknown. This project examined the dose-dependent effects of a combined resveratrol intervention with exercise training on circulating TMAO and other related metabolite signatures in older adults with high CVD risk. Methods: Forty-one older adults [mean (±SD) age of 72.1 (6.8) years] participated in a 12-week supervised center-based, multi-component exercise training intervention [2×/week; 80 min/session] and were randomized to one of two resveratrol dosages [Low: 500 vs. High:1000 mg/day] or a cellulose-based placebo. Serum/plasma were collected at baseline and post-intervention and evaluated for TMAO and associated analytes. Results: After the 12-week intervention, TMAO concentration increased over time, regardless of treatment [mean (±SD) Placebo: 11262 (±3970); Low:13252 (±1193); High: 12661(±3359) AUC; p = 0.04]. Each resveratrol dose produced different changes in metabolite signatures. Low dose resveratrol upregulated metabolites associated with bile acids biosynthesis (i.e., glycochenodeoxycholic acid, glycoursodeoxycholic acid, and glycocholic acid). High dose resveratrol modulated metabolites enriched for glycolysis, and pyruvate, propanoate, β-alanine, and tryptophan metabolism. Different communities tightly correlated to TMAO and resveratrol metabolites were associated with the lipid and vascular inflammatory clinical markers [|r| > 0.4, p |
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