# Gut–Heart Axis in HFpEF: The Emerging Role of Microbiome-Driven Inflammation and Endothelial Dysfunction

## TL;DR

This paper reviews how gut microbiome changes may contribute to heart failure with preserved ejection fraction through inflammation and endothelial dysfunction.

## Contribution

It introduces a novel framework linking gut microbiome dysregulation to HFpEF pathophysiology and potential therapeutic strategies.

## Key findings

- Gut dysbiosis contributes to systemic inflammation and endothelial dysfunction via bacterial metabolites and lipopolysaccharide translocation.
- Microbiome-targeted interventions like probiotics and fecal microbiota transplantation show therapeutic potential in HFpEF.
- Short-chain fatty acids, TMAO, and bile acids are key metabolites involved in gut-heart axis mechanisms.

## Abstract

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.