In spite of the evolution of lipid-lowering therapies, the presence of persistent, chronic inflammation continues to drive cardiovascular disease risk independent of lipid biomarkers. Studies have demonstrated improved atherosclerotic outcomes when inflammation itself is directly targeted on top of blood lipids. Identification of the upstream source of dysfunctional inflammatory resolution remains the predominant challenge of delivering tailored treatments. The role of the microbiome in the regulation of the inflammatory response is well established in the research literature. Microbial disorder is now recognized as a hallmark of the aging process and is additionally correlated with progression of other disease pathologies. The critical link between gut dysbiosis and immune activation makes restoring microbiome balance a primary strategy for attenuating inflammatory burden and mitigating cardiovascular disease.
Dysbiosis is potentiated by metabolic stress, environmental exposures, and disease progression that induce loss of immunosurveillance and consequent shifts in microbial populations. Pathogenic bacteria predominate and alter metabolic balance and metabolite production. The gut barrier relies upon microbiome homeostasis to manage inflammatory tone, produce anti-inflammatory molecules, and maintain mucosal cell viability. As the integrity of the intestinal lining is compromised, harmful compounds including metabolites and endotoxins from resident bacteria leach through the intestinal lumen. These substances induce oxidative stress, trigger an immune response, and facilitate immune reprogramming. The result is impaired resolution of low-level, festering inflammation that induces endothelial dysfunction and vascular damage which promote atherosclerosis.
Trimethylamine (TMA) is a gut-microbiota-derived metabolite produced upon digestion of choline, carnitine, and lecithin. TMA travels from the gut to the liver where it is converted into trimethylamine N-oxide (TMAO). TMAO has been observed to set off pro-inflammatory pathways in vascular and immune cells that contribute to atherosclerosis progression. TMAO inhibits reverse cholesterol transport while increasing expression of macrophage scavenger receptors like CD36 that amplify uptake of oxidized LDL. TMAO also prompts oxidative stress in the endothelium, contributing to the activation of NF-kB/MAPK signaling and the NLRP3 inflammasome. This cascade gives rise to foam cells as immune cells infiltrate the injured tissue to control the damage.
Short-chain-fatty acids (SCFAs) are abundantly produced by commensal bacteria and serve a fundamental role in immunoregulation. Generated during the fermentation process of indigestible carbohydrates, SCFAs exhibit profound anti-inflammatory activity and act as a primary fuel substrate for both intestinal epithelial cells and the endothelial cells of the blood brain barrier and vasculature. In the vasculature, SCFAs also induce vasodilation. SCFAs additionally function as signaling metabolites, inhibiting histone deacetylases and stimulating G-protein-coupled receptors involved in cellular metabolism. Their presence enhances immune cell and redox balance, T-cell differentiation, and expression of tight junction proteins. Finally, adequate SCFA concentrations attenuate NF-kB activation as well as the pro-inflammatory signals introduced by TMAO and lipopolysaccharide.
The renin-angiotensin system is also postulated to be disturbed by microbial dysbiosis, perpetuating reactive oxygen species generation, NF-kB activation, and vascular remodeling. Furthermore, disrupted microbial metabolism diminishes aryl hydrocarbon receptor signaling that ordinarily reinforces immune balance, epithelial integrity, and IL-22-related barrier support. The immune reprogramming potentiated by ongoing dysbiosis and inflammatory signals drives atherogenic progression. Immune cell balance becomes skewed toward an inflammatory phenotype, and overzealous immune cells attack oxidized lipids, promoting vascular injury and plaque development.
Lifestyle and dietary choices play a large part in mitigating dysbiosis and restoring microbial homeostasis. A diet rich in indigestible fibers can bolster SCFA production, thereby reinstating gut barrier integrity and inflammatory tone. Polyphenols, dietary fiber, and monounsaturated fatty acids abundant in a Mediterranean dietary pattern enhance microbial diversity and promote proliferation of SCFA-producing commensals. Metabolic function is improved following this approach, leading to a reduction in oxidative stress and inflammatory signaling, and amelioration of mitochondrial performance and immune regulation.
A healthy population of commensal bacteria serves to crowd-out pathogenic strains, thereby attenuating their pro-inflammatory potential. Precision pre- and probiotics can facilitate microbial homeostasis by supporting growth of certain bacterial strains. The gut dysbiosis-systemic inflammation-atherosclerosis link is mechanistically sound. However, questions and controversy persist concerning the precise nature of the relationship between cardiovascular disease risk and key metabolites such as TMAO, dysbiosis, and gut-directed therapeutic interventions. While research is ongoing, restoration of microbial homeostasis through appropriate dietary and lifestyle interventions nevertheless remains a valid objective for overall host health.
Song D, Gao H, Wang T, Wei Q, Liu A, Ren J. Gut microbiota dysbiosis-induced chronic inflammation as a driver of atherosclerosis: cellular crosstalk and host-microbe interactions. Front Cell Infect Microbiol. 2026;16:1789194. Published 2026 May 15. doi:10.3389/fcimb.2026.1789194