Atherosclerosis

TMAO and Foam Cell Formation#

Gut bacteria convert dietary choline, phosphatidylcholine, and L-carnitine to trimethylamine (TMA) via cutC/cutD genes.

Hepatic FMO3 oxidizes TMA to Trimethylamine N-Oxide (TMAO), which promotes cholesterol deposition in macrophages, creating foam cells—the hallmark of early plaque.^{[1]Role of the intestinal microbiome and its therapeutic intervention in cardiovascular disorderAmeer Luqman, Adil Hassan, Mehtab Ullah et al. · 2024Open reference 1 ↓}

TMAO also enhances platelet hyperreactivity and thrombosis risk.

Bacteria in Atherosclerotic Plaques#

Oral bacteria translocate to arterial plaques: Porphyromonas gingivalis, Fusobacterium nucleatum, Aggregatibacter actinomycetemcomitans, and oral Streptococcus spp. have been detected in atherosclerotic tissue.^{[2]Microbiome and Cardiovascular DiseaseHilde Herrema, Max Nieuwdorp, Albert K. Groen · 2020Open reference 2 ↓}

Periodontitis is an independent risk factor for ASCVD; the CANTOS trial confirmed the central role of IL-1-beta-driven inflammation. FMT from atherosclerotic mice induces atherosclerosis in recipients, demonstrating causal microbial contribution.

Gut Dysbiosis in ASCVD#

ASCVD patients show decreased Bacteroidetes (Bacteroides, Prevotella) and enrichment of Enterobacteriaceae. Reduced SCFA production impairs anti-inflammatory Treg responses and gut barrier integrity. Fungal dysbiosis: Candida albicans, Exophiala, Malassezia enriched in coronary artery disease; Mucor racemosus depleted.^{[3]Gut mycobiome in cardiometabolic disease progression: current evidence and future directionsXiaoyu Wei, Zixin Guo, Jingyang Wang et al. · 2025Open reference 3 ↓}

Copper#

copper (Cu) is elevated in atherosclerotic plaques; catalyzes LDL oxidation via Fenton-like reactions, accelerating foam cell formation. Ceruloplasmin (copper-containing) is an acute-phase protein elevated in cardiovascular inflammation.

Lead and Cadmium#

lead (Pb) exposure is an independent risk factor for cardiovascular mortality even at low blood levels. cadmium (Cd) promotes endothelial dysfunction, oxidative LDL modification, and smooth muscle cell proliferation. Both metals drive dysbiosis that further increases TMAO production and reduces protective SCFA output.

Iron#

Free iron in plaques generates ROS via Fenton chemistry, oxidizing LDL and destabilizing plaques. Hepcidin dysregulation in chronic inflammation alters systemic iron distribution.

Protective Metabolites#

Short-Chain Fatty Acids (SCFAs): Propionate and Butyrate are generally cardioprotective—anti-inflammatory, blood pressure-lowering via GPR41/Olfr78 balance. butyrate: HDAC inhibition reduces macrophage inflammatory activation. Secondary bile acids: FXR/TGR5 signaling modulates cholesterol metabolism.