Gut Microbiota and Short-Chain Fatty Acids in Cardiometabolic HFpEF: Mechanistic Pathways and Nutritional Therapeutic Perspectives

Heart failure with preserved ejection fraction (HFpEF) accounts for more than half of the cases of HF worldwide. Among the different phenotypes, cardiometabolic HFpEF has the highest prevalence. Cumulative insults related to cardiometabolic comorbidities-obesity, hypertension and type 2 diabetes-create a milieu of metabolic derangements, low-grade systemic inflammation (i.e., metainflammation), endothelial dysfunction, and coronary microvascular disease. Emerging data indicate that the gut-heart axis is a potential amplifier of this process. Cardiometabolic comorbidities promote gut dysbiosis, loss of short-chain fatty acid (SCFA)-producing taxa, and disruption of the intestinal barrier, leading to endotoxemia and upregulation of pro-inflammatory pathways such as TLR4- and NLRP3-mediated signaling. Concomitantly, beneficial gut-derived metabolites (acetate, propionate, butyrate) decrease, while detrimental metabolites increase (e.g., TMAO), potentially fostering myocardial fibrosis, diastolic dysfunction, and adverse remodeling. SCFAs-acetate, propionate, and butyrate-may exert pleiotropic actions that directly target HFpEF pathophysiology: they may provide a CPT1-independent energy substrate to the failing myocardium, may improve lipid and glucose homeostasis via G protein-coupled receptors and AMPK activation, and may contribute to lower blood pressure and sympathetic tone, reinforce gut barrier integrity, and act as anti-inflammatory and epigenetic modulators through the inhibition of NF-κB, NLRP3, and histone deacetylases. This review summarizes current evidence linking gut microbiota dysfunction to cardiometabolic HFpEF, elucidates the mechanistic role of SCFAs, and discusses nutritional approaches aimed at enhancing their production and activity. Targeting gut-heart axis and SCFAs pathways may represent a biologically plausible and low-risk approach that could help attenuate inflammation and metabolic dysfunctions in patients with cardiometabolic HFpEF, offering novel potential therapeutic targets for their management.