The Heart–Gut Axis in Heart Failure: The Role of Next-Generation Pharmacological Therapies

Heart failure (HF) is a systemic syndrome in which cardiac dysfunction is closely linked to multiorgan involvement, including the gastrointestinal tract. Increasing evidence highlights the relevance of the gut–heart axis in HF pathophysiology, whereby intestinal hypoperfusion, congestion, and barrier dysfunction promote gut microbiota dysbiosis, systemic inflammation, and adverse cardiovascular outcomes. In parallel, the advent of novel HF therapies, particularly sodium–glucose cotransporter 2 inhibitors (SGLT2i) and the angiotensin receptor–neprilysin inhibitor sacubitril/valsartan, has markedly improved clinical outcomes across HF phenotypes. Beyond their established cardiovascular benefits, these therapies may exert pleiotropic effects that extend to the intestinal environment and the gut microbiota. Through integrated actions on hemodynamics, neurohormonal activation, metabolic pathways, and inflammatory processes, recent data suggest that novel HF drugs may indirectly influence the gut-microbial composition and function. Conversely, the gut microbiota may modulate drug efficacy and result in interindividual variability in therapeutic responses, suggesting a bidirectional interaction between pharmacological treatment and the gut ecosystem. This narrative review summarizes current evidence of gut microbiota alterations in HF and critically examines emerging data on interactions between the gut microbiota and novel HF therapies, focusing on SGLT2 inhibitors and sacubitril/valsartan. Understanding this crosstalk may support the development of microbiota-informed, personalized therapeutic strategies in heart failure.