Gut Microbiota in Heart Failure with Preserved Ejection Fraction: Clinical Phenotyping and Therapeutic Opportunities.

Background/Objectives: In heart failure with preserved ejection fraction (HFpEF), the gut-heart axis has emerged as a potential contributor to inflammation and cardiometabolic stress. We characterised gut microbiota composition, diversity, and predicted metabolic potential in HFpEF to assess their associations with disease status and clinical heterogeneity. Methods and Results: Faecal samples from 30 HFpEF patients and 28 healthy controls were profiled by means of bacterial ribosomal RNA gene sequencing. The groups were comparable in age (74 years in both groups) and sex (female: 60% vs. 60.7%). HFpEF patients exhibited lower community evenness (p = 0.04) and a trend toward lower diversity (p = 0.08), but no detectable shift in global community structure. The tested clinical and demographic variables explained only a modest proportion of the observed variation in community structure, with substantial residual variation across the beta-diversity analyses. No taxa were differentially abundant between groups at the predefined thresholds. Among clinical stratifications, New York Heart Association (NYHA) class showed the most consistent family-level associations, including stepwise depletion of Lachnospiraceae, Butyricicoccaceae, and Ruminococcaceae and enrichment of Akkermansiaceae; Enterobacteriaceae peaked in milder disease. These severity-associated taxonomic trajectories were accompanied by predicted functional shifts consistent with microbial adaptation to increasing metabolic constraints, including enrichment of stress-adaptation traits and, with increasing functional limitation, depletion of core metabolic and fermentative pathways and relative enrichment of oxidative stress-response pathways. Conclusions: HFpEF is associated with subtle gut microbiota alterations that appear to reflect severity- and context-dependent ecological reorganisation rather than uniform dysbiosis. These findings support severity-informed approaches targeting microbial metabolic function and ecological context rather than broad compositional changes.