Atherosclerosis

Progressive inflammatory disease of the arterial wall characterized by lipid accumulation, immune cell infiltration, and fibrous plaque formation. In the metallomics framework, atherosclerosis sits at the convergence of three interacting systems: heavy metal toxicity, gut/oral microbial dysbiosis, and chronic inflammation.

The Microbiome-Atherosclerosis Axis

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 tmao, which promotes cholesterol deposition in macrophages, creating foam cells -- the hallmark of early plaque [luqman 2024 intestinal microbiome cvd intervention].
- 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 [herrema 2020 microbiome cardiovascular disease ascvd].
- 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 [wei 2025 gut mycobiome cardiometabolic disease].

Metal Contributions to Atherosclerosis

Copper

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

Lead and Cadmium

- Pb exposure is an independent risk factor for cardiovascular mortality even at low blood levels.
- 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: 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.