Abstract
The gut microbiome is known to modulate metabolic health, yet its role in coronary heart disease (CHD) and heart failure with preserved ejection fraction (HFpEF) remains unclear. In the present study, we profiled the gut microbiome of 234 participants using shotgun metagenomic sequencing across controls ( n = 43), individuals with low-risk atherosclerosis (LRAS, n = 23), and patients with CHD + HFpEF ( n = 168). Species richness was significantly increased in CHD + HFpEF, with no disruption in taxonomic evenness. LRAS did not diverge significantly in alpha metrics. In contrast, beta diversity analysis demonstrated significant divergence of both LRAS and CHD + HFpEF taxonomic structure from controls, with the greatest divergence in CHD + HFpEF, particularly in older patients. Notably, all differences were attenuated when comparing obese controls and disease groups. However, significant heterogeneity in multivariate dispersion was observed, and a contribution of differences in variation cannot be excluded. Further differential analysis, adjusting for age, BMI, sex, and glucose and lipid profiles, revealed significant associations between specific taxa and CHD + HFpEF, including depletion of the saccharolytic fermenter Bifidobacterium and enrichment of taxa linked to proteolytic or inflammatory metabolism (notably Prevotella and Bilophila ), regardless of age and BMI. Subsequent analysis of inferred functional features indicated increased potential for L-citrulline, L-glutamate, L-lysine, and pyrimidine metabolism in CHD + HFpEF. Collectively, the present analysis suggests that CHD + HFpEF is associated with distinct compositional and functional shifts in the gut microbiome. Further longitudinal and interventional research is required to determine which of these microbial features contribute to disease progression and to better characterize underlying mechanisms.