Role of Gut Microbiota in Diabetic HFpEF: Mechanisms and Therapeutic Implications

Heart failure with preserved ejection fraction (HFpEF) is rapidly emerging as a predominant form of heart failure worldwide. Its pathogenesis extends beyond traditional hemodynamic abnormalities and involves multiple pathways, such as systemic metabolism, inflammation, and endothelial dysfunction. Type 2 diabetes mellitus (T2DM), which is present in up to 45% of patients with HFpEF, is one of the most common and clinically important comorbidities of HFpEF. T2DM not only significantly increases its incidence but also leads to more severe complications and poorer prognosis, constituting a distinct clinical phenotype known as "diabetic HFpEF." In recent years, the role of the gut microbiota (GMB) as a central hub linking metabolism and the cardiovascular system has become increasingly prominent. This review summarizes the epidemiological and pathophysiological connections between T2DM and HFpEF, with a focus on characteristic alterations in gut dysbiosis in patients with diabetic HFpEF and the underlying mechanisms involving microbiota-derived metabolites, including short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), and bile acids (BAs). It also discusses how the cardiovascular protective effects of novel antidiabetic drugs are closely related to their potential mechanisms of modulating gut microbiota ecology and restoring metabolic balance. However, current evidence remains largely mechanistic and observational, and the causal relationships between gut dysbiosis and diabetic HFpEF require further validation. Overall, GMB represents an important and modifiable target in patients with diabetic HFpEF, offering new directions for both mechanistic research and therapeutic interventions.