The Role of Firmicutes in Coronary Artery Disease: A Taxonomic-Level Meta-Analysis of Mendelian Randomization Studies

The Gut Microbiome (GM) plays a critical role in cholesterol metabolism through the production of metabolites such as trimethylamine N-oxide and shortchain fatty acids, contributing to inflammation, endothelial dysfunction, and host gene regulation. This study aims to taxonomically characterize gut microbial profiles, evaluate their association with coronary artery disease, and explore the potential therapeutic implications of microbiome- mediated cardiometabolic pathways.

We pooled data from six Mendelian Randomization studies that utilized the MiBio- Gen consortium and CAD, and cardiovascular risk GWAS data from CARDIoGRAMplusC4D, FinnGen, and UK Biobank databases. Within the phylum Firmicutes, inverse variance weighted analysis was used to estimate the association between: (1) protective effects of Clostridiales vadinBB60 group, Genus Butyricicoccus, Genus Ruminococcus UCG010, Coprococcus 1, Intestinibacter, Ruminiclostridium 6, Anaerotruncus, and Family Acidaminococcaceae; and (2) causative effects of Clostridium innocuum group, Genus Turicibacter, Eisenbergiella, Holdemanella, Eubacterium, Coprostanoligenes group, Ruminococcaceae UCG005, and Genus Catenibacterium on CAD.

Higher levels of phylum Firmicutes exhibit a statistically significant protective effect on CAD (OR: 0.880, 95% CI: 0.853-0.907), with low heterogeneity (I² = 20%, P = 0.857). Conversely, an increased abundance of Firmicutes also correlates with a higher risk of CAD (OR: 1.10, 95% CI: 1.06-1.14), showing low heterogeneity (I² = 20%, P = 0.90). Leave-one-out sensitivity analyses confirmed the robustness of these results.

The findings highlight a significant relationship between gut microbiome dysbiosis and adverse cardiometabolic outcomes, potentially mediated through inflammatory pathways, metabolic signaling, and microbial metabolite production. These results support the growing role of microbiome-targeted interventions as emerging strategies for cardiometabolic risk modification.

Firmicutes exhibit both protective and causative effects on CAD. These findings highlight the complexity of the gut microbiome's role in cardiovascular diseases. Further detailed research on the mechanisms by which specific bacteria at the lower taxonomic levels exert this effect is imperative to understand this complex relationship and its clinical implications.