Heart failure with preserved ejection fraction (HFpEF) represents the predominant form of heart failure, affecting over 50% of all heart failure patients with increasing prevalence in aging populations. Despite significant advances in cardiovascular medicine, HFpEF remains a complex clinical syndrome with poorly understood pathophysiology and limited treatment options. While most studies have traditionally focused on the renin–angiotensin–aldosterone system (RAAS) and other related mechanisms, emerging evidence has unveiled a critical bidirectional relationship between dysregulation of gut microbiota and HFpEF development. This phenomenon, mediated through microbiome-driven inflammation and endothelial dysfunction, introduces a novel concept and potential emerging conceptual framework in understanding HFpEF. This comprehensive review explores this novel gut–heart axis by synthesizing the latest evidence from original studies and clinical trials. We discuss novel mechanisms involving bacterial metabolites, including short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), bile acids, and amino acid derivatives. We also examine how gut dysbiosis may contribute to systemic inflammation through lipopolysaccharide translocation, NLRP3 inflammasome activation, and endothelial dysfunction. Furthermore, clinical trials investigating microbiome-targeted interventions, including probiotics, fecal microbiota transplantation, metabolite supplementation, and precision medicine approaches, are critically evaluated for their therapeutic potential. This review provides a framework for hypothesis generation and future research directions about therapeutic strategies targeting the gut–heart axis in HFpEF management.

Heart failure with preserved ejection fraction (HFpEF) represents the predominant form of heart failure, affecting over 50% of all heart failure patients with increasing prevalence in aging populations. Despite significant advances in cardiovascular medicine, HFpEF remains a complex clinical syndrome with poorly understood pathophysiology and limited treatment options. While most studies traditionally focused on the renin-angiotensin-aldosterone system (RAAS) and other related mechanisms, emerging evidence has unveiled a critical bidirectional relationship between dysregulation of gut microbiota and HFpEF development. This phenomenon, mediated through microbiome-driven inflammation and endothelial dysfunction, introduces a novel concept and potential paradigm shift in understanding HFpEF. This comprehensive review explores this novel gut-heart axis by synthesizing the latest evidence from original studies and clinical trials. We discuss novel mechanisms involving bacterial metabolites, including short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), bile acids, and amino acid derivatives. We also examine how gut dysbiosis contributes to systemic inflammation through lipopolysaccharide translocation, NLRP3 inflammasome activation, and endothelial dysfunction. Furthermore, clinical trials investigating microbiome-targeted interventions, including probiotics, fecal microbiota transplantation, metabolite supplementation, and precision medicine approaches, are critically evaluated for their therapeutic potential. This review provides a roadmap for future research and therapeutic strategies targeting the gut-heart axis in HFpEF management.

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.

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). This state-of-the-art narrative review synthesizes evidence from 14 observational studies (13 prospective cohorts and one cross-sectional analysis), encompassing a heterogeneous range of HF settings, including established chronic HF, acute decompensated HF, incident HF in community cohorts, and subclinical myocardial injury. Across these populations, elevated circulating TMAO has been associated with adverse outcomes, including mortality, rehospitalization, and major adverse cardiovascular events, although the strength and consistency of associations vary by HF phenotype, renal function status, and population ancestry. The prognostic independence of TMAO is attenuated after adjusting for renal function in several cohorts, reflecting both obligatory renal clearance and a potentially bidirectional relationship with kidney injury. TMAO was not reduced during neurohormonal GDMT uptitration in the BIOSTAT-CHF study, suggesting that gut microbiota dysbiosis may represent a pathophysiological axis not reached by current HF treatment. The field has evolved through three thematic stages: TMAO as a single prognostic biomarker, TMAO within cardiorenal pathophysiology, and multimetabolite and multipathway risk profiling. Beyond the TMAO pathway, emerging evidence for phenylacetylglutamine (PAGln), short-chain fatty acids (SCFAs), and protein-bound uremic toxins as parallel gut-derived cardiovascular mediators supports a multidimensional metabolite profiling approach. Several cohorts suggest that selected multimetabolite panels may provide additional prognostic information beyond TMAO alone, although their composition, calibration, and external validity remain uncertain. Population-specific variation in TMAO levels and prognostic thresholds complicates universal clinical 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 multimetabolite panels across diverse populations, and conducting intervention trials targeting the gut–heart–kidney axis.