The Gut-Heart Axis: How Microbes Affect Cardiovascular Disease

Adriano dos Santos
Sep 29
6 min read

When we think about heart health, the conversation often stops at cholesterol, blood pressure, and exercise. But there’s a deeper layer that quietly shapes inflammation, metabolism, and even how stable your arteries remain over time. Ignoring it could mean missing a critical piece in preventing heart disease before it starts.

For years, cardiovascular disease was viewed almost entirely through the lens of cholesterol levels, blood pressure, and arterial plaque. But a growing body of research reveals that the gut microbiome, the trillions of bacteria, fungi, and other microorganisms living in our intestines, is increasingly recognised as linked to cardiovascular health (Wilson Tang W.H. et al., 2017). Its influence extends far beyond digestion, affecting immune responses, nutrient processing, and the stability of arterial plaques.

When in balance, the microbiome produces beneficial metabolites such as short-chain fatty acids (SCFAs) that protect the vascular system and support metabolic health (Chambers E. et al., 2018). When disrupted, it can generate compounds trimethylamine N-oxide (TMAO), where higher levels have been associated with vulnerable plaque features and adverse events in several studies; causal roles are still being investigated (Datta S. et al., 2024).

TMAO is formed when gut microbes metabolise choline, betaine, or carnitine from foods like red meat, eggs, fish, and dairy, before being converted by hepatic FMO3 into its circulating form. Plasma TMAO concentrations in healthy adults typically range between 2.5 and 4.0 μmol/L, but may rise more than 20-fold in people with kidney dysfunction due to impaired clearance (Circulating trimethylamine N-oxide and cardiovascular, cerebral, and renal diseases including mortality: Umbrella review of published systematic reviews and meta-analyses).

Human observational studies have reported associations between elevated TMAO and cardiovascular disease, type 2 diabetes, impaired kidney function, and all-cause mortality. However, not all studies confirm these findings, and adjustment for renal function often weakens or abolishes the associations, suggesting kidney dysfunction is a major confounder (Circulating trimethylamine N-oxide and cardiovascular, cerebral, and renal diseases including mortality: Umbrella review of published systematic reviews and meta-analyses).

Human data are partly observational; mechanistic and interventional evidence is growing but not definitive.

In my own work, I’ve seen patients with “good” lipid panels and normal blood pressure still progress towards significant cardiovascular disease, and the missing clue often lies in their gut health profile. This is why I often check apoB alongside LDL-C, since apoB better reflects the number of atherogenic particles when results are discordant. This is why I no longer see cardiovascular care as separate from digestive health; the two are deeply intertwined.

Why the Gut–Heart Connection Matters

Cardiovascular disease remains the leading cause of mortality worldwide. Dysbiosis, an imbalance in the gut microbiota, is now associated with coronary artery disease, heart failure, and plaque vulnerability (Trøseid M. et al., 2020; Shen X. et al., 2021. This connection is not a minor factor; it influences disease onset, progression, and recovery.

Research shows that an altered microbiota can promote systemic inflammation, impair lipid metabolism, and reduce the production of protective short-chain fatty acids (Chambers E. et al., 2018). Elevated levels of harmful metabolites like TMAO have been linked to accelerated plaque formation and reduced plaque stability, although causality in humans remains uncertain (Datta S. et al., 2024).

Umbrella reviews show that elevated plasma TMAO has been associated with cardiovascular disease, stroke, kidney disease, and major adverse cardiovascular events, but the quality of evidence remains low. Many included studies were observational, with heterogeneous populations, inconsistent definitions of outcomes, and inadequate adjustment for confounders. No randomised controlled trials have yet demonstrated that lowering TMAO improves outcomes (Circulating trimethylamine N-oxide and cardiovascular, cerebral, and renal diseases including mortality: Umbrella review of published systematic reviews and meta-analyses).

Additionally, the gut–heart relationship appears to be bidirectional: cardiovascular disease can further disrupt the microbiome, creating a vicious cycle that exacerbates disease progression (Wilson Tang W.H. et al., 2017).

From a clinical perspective, this bidirectionality is crucial. I’ve observed that when we treat the heart without addressing the gut, progress is often slower, and relapses are more common. But when we support both simultaneously, inflammation decreases faster, patients feel better sooner, and long-term stability improves. Inflammation itself is now an independent therapeutic target: the CANTOS trial validated that lowering inflammation with canakinumab reduced events without changing LDL-C.

Imaging tools such as coronary artery calcium (CAC) scoring or carotid ultrasound can help identify subclinical disease when “normal labs” hide residual risk.

Mechanisms Linking the Gut and the Heart

From a clinical perspective, three mechanisms stand out:

Inflammation and Immune Modulation – Dysbiosis can provoke chronic low-grade inflammation, destabilising plaques and damaging the endothelium (Shen X. et al., 2021).
Microbial Metabolites – Protective SCFAs help regulate vascular tone and blood pressure, while harmful metabolites such as TMAO accelerate atherosclerosis (Chambers E. et al., 2018; Datta S. et al., 2024).
Metabolic Regulation – The microbiome plays a role in lipid and glucose metabolism, impacting long-term cardiovascular outcomes (Trøseid M. et al., 2020).

Proposed mechanisms for TMAO’s potential role include vascular inflammation, macrophage foam cell formation, thrombosis, and renal fibrosis, but these derive largely from animal studies and may not directly apply to humans (Circulating trimethylamine N-oxide and cardiovascular, cerebral, and renal diseases including mortality: Umbrella review of published systematic reviews and meta-analyses).

These mechanisms aren’t just theory, I apply them daily in my practice, using microbiome sequencing, metabolite testing, and inflammatory markers to match the right protocol to each patient.

Nutraceutical Protocols and Therapeutic Perspectives

Addressing the gut–heart connection requires a targeted approach:

Prebiotic fibres from legumes, oats, berries, and leafy greens to stimulate SCFA production (Chambers E. et al., 2018)
Polyphenol-rich foods such as green tea, pomegranate, and cacao to modulate microbiota composition and reduce oxidative stress (Wilson Tang W.H. et al., 2017)
Probiotic supplementation with strains supporting endothelial function and inflammation control (Trøseid M. et al., 2020)
Omega-3 fatty acids for lipid balance and vascular anti-inflammatory effects (Datta S. et al., 2024)
Berberine to help regulate glucose metabolism and lipid levels (Wilson Tang W.H. et al., 2017)

At present, there are no established interventions proven to lower plasma TMAO concentrations in humans, and measuring TMAO is not part of routine clinical practice. Small trials with probiotics, synbiotics, or dietary shifts have not consistently reduced TMAO or improved surrogate markers of atherosclerosis (Circulating trimethylamine N-oxide and cardiovascular, cerebral, and renal diseases including mortality: Umbrella review of published systematic reviews and meta-analyses).

Case Study: Supporting Plaque Stability Through Microbiome Modulation

A 62-year-old patient with asymptomatic carotid artery plaques underwent microbiome testing, which revealed low levels of butyrate-producing bacteria and an overrepresentation of TMAO-associated species (Datta S. et al., 2024). Baseline labs showed elevated apoB and Lp(a), with hs-CRP at 4.8 mg/L.

A protocol was introduced combining increased dietary fibre, specific probiotic strains, and daily polyphenol supplementation, alongside moderate exercise. At 3 months, hs-CRP had dropped to 1.6 mg/L, fitness and energy improved, and symptoms such as exertional fatigue lessened. Imaging showed no plaque progression, which is consistent with stability rather than rapid regression.

Longer-term follow-up with carotid ultrasound and CAC is recommended to confirm outcomes on harder endpoints.

Conclusion

The gut and heart are closely connected. While much of the human evidence remains associative, integrating microbiome assessment with markers like apoB, hs-CRP, and CAC can uncover hidden risks and guide more personalised care.

At the same time, umbrella reviews caution that evidence linking TMAO with cardiovascular and renal outcomes is low confidence, confounded by kidney function, and not enough to prove causality. More studies are needed before TMAO becomes a therapeutic target (Circulating trimethylamine N-oxide and cardiovascular, cerebral, and renal diseases including mortality: Umbrella review of published systematic reviews and meta-analyses).

For clinicians, the message is twofold: continue leveraging established tools for risk detection, and stay attentive to the evolving science of the microbiome. This combined approach may not only slow disease progression but also help restore resilience and improve long-term outcomes.

References:

Wilson Tang W.H., Kitai T., Hazen S. (2017). Gut Microbiota in Cardiovascular Health and Disease. Circulation Research. American Heart Association Journals. doi: 10.1161/CIRCRESAHA.117.309715
Trøseid M., Øystein Andersen G., Broch K., Roksund Hov J. (2020). The gut microbiome in coronary artery disease and heart failure: Current knowledge and future directions. eBioMedicine. DOI: 10.1016/j.ebiom.2020.102649
Chambers E., Preston T., Frost G., Morrison D. (2018). Role of Gut Microbiota-Generated Short-Chain Fatty Acids in Metabolic and Cardiovascular Health. Springer Nature. doi: 10.1007/s13668-018-0248-8
Shen X., Li L., Sun Z., Zang G., Zhang L., Shao C., Wang Z. (2021). Gut Microbiota and Atherosclerosis—Focusing on the Plaque Stability. Frontiers in Cardiovascular Medicine. https://doi.org/10.3389/fcvm.2021.668532
Datta S., Pasham S., Inavolu S., Boini K., Koka S. (2024). Role of Gut Microbial Metabolites in Cardiovascular Diseases—Current Insights and the Road Ahead. International Journal of Molecular Sciences. https://doi.org/10.3390/ijms251810208
Obeid R., Mohr L., White B., Heine G., Emrich I., Geisel J., Carter C. (2025). Circulating trimethylamine N-oxide and cardiovascular, cerebral, and renal diseases including mortality: Umbrella review of published systematic reviews and meta-analyses. ScienceDirect. https://doi.org/10.1016/j.numecd.2025.103908