Trimethylamine N-oxide in exercise physiology: a gut microbiota-derived signal linking metabolic stress, redox balance and cardiometabolic health

Abstract Trimethylamine N-oxide (TMAO) is a gut microbiota-derived metabolite traditionally associated with cardiovascular and metabolic disease risk; however, emerging evidence from exercise physiology and metabolomics suggests a more complex and context-dependent biological role. This narrative review synthesizes findings from human observational studies, exercise interventions, supplementation trials, and animal models to examine TMAO metabolism, physiological functions, and its relationship with physical activity, training adaptations, and metabolic stress. Circulating TMAO concentrations are determined primarily by dietary precursor availability, gut microbial metabolism, hepatic flavin monooxygenase activity, and renal clearance. Across human studies, TMAO levels do not consistently correlate with aerobic fitness, habitual physical activity, or training status. Exercise-only interventions rarely produce significant changes in circulating TMAO concentrations, whereas dietary manipulation and precursor supplementation exert substantially stronger effects. Experimental evidence nevertheless suggests that TMAO may exert context-dependent biological actions related to protein stabilization, mitochondrial energy metabolism, redox regulation, and tolerance to physiological stress. Acute endurance exercise, high training load, and exercise-induced muscle damage have also been associated with transient alterations in circulating or urinary TMAO levels, although findings remain limited and heterogeneous. Collectively, current evidence does not support interpreting TMAO solely as a pathogenic metabolite. Instead, circulating TMAO may reflect interactions among diet, gut microbiota activity, metabolic stress, and host physiological status. However, the usefulness of TMAO or the TMAO/TMA ratio as biomarkers of exercise adaptation, training load, or recovery remains to be established in controlled longitudinal human studies.