The Gut-Heart-Kidney Axis in Heart Failure: Trimethylamine N-Oxide and Beyond, A State-of-the-Art Review

Trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite of dietary choline and L-carnitine, has emerged as a leading molecular mediator of the gut-heart-kidney axis in heart failure (HF). Evidence from 14 prospective cohort studies demonstrates consistent associations between elevated circulating TMAO and adverse outcomes including mortality, rehospitalization, and major adverse cardiovascular events. The prognostic independence of TMAO is attenuated after renal function adjustment, reflecting both obligate renal clearance and a bidirectional relationship with kidney injury. Critically, TMAO is not modulated by conventional neurohormonal guideline-directed medical therapy (GDMT), suggesting that gut microbiome dysbiosis represents a pathophysiological axis not reached by current HF treatment. The field has evolved through three conceptual eras: TMAO as a single prognostic biomarker, TMAO as a cardiorenal mediator, and most recently, TMAO as the anchor of a multi-metabolite gut-heart signature encompassing trimethyllysine, choline, crotonobetaine, and acetyl-L-carnitine. Beyond the TMAO pathway, emerging evidence for phenylacetylglutamine, short-chain fatty acids, and protein-bound uremic toxins as parallel gut-derived cardiovascular mediators supports a multidimensional metabolite profiling approach. Panel approaches consistently outperform single-marker TMAO. Ethnic and dietary heterogeneity complicate universal threshold application. Without human interventional data demonstrating that lowering TMAO improves cardiovascular outcomes, TMAO remains a prognostic risk marker rather than a validated clinical target. Clinical translation requires resolving the renal confounding problem, validating multi-metabolite panels across diverse populations, and conducting intervention trials targeting the gut-heart-kidney axis.