Gut Microbiota and Cardiovascular Diseases: Unraveling the Role of Dysbiosis and Microbial Metabolites
Abstract
1. Introduction
2. Human Microbial Contributions
3. Cardiovascular Diseases (CVDs) and Gut Microbiota
4. HFs and Gut Microbial Changes
5. Hypertension and Gut Microbial Changes
6. Myocardial Infarction and Gut Dysbiosis
7. Atherosclerosis and Gut Microbiota Composition
8. Natural Products and Their Potential in CVD
8.1. Flavonoids
8.2. Omega-3 Fatty Acids
8.3. Resveratrol
8.4. Curcumin
8.5. Coenzyme Q10 (CoQ10)
8.6. Marine-Derived Compounds
9. Natural Products as Microbial Modulators for Cardioprotection
10. Synergistic Effects of Phytochemicals in CVD
11. Challenges and Future Directions
12. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Metabolite | Activated Pathway | Key Effects | Impact on Heart Failure |
---|---|---|---|
SCFAs (acetate, propionate, butyrate) | GPR41, GPR43, GPR109A activation; HDAC inhibition | ↑ IL-10 (anti-inflammatory cytokine), ↓ systemic inflammation, improved gut barrier integrity | Protective: maintains epithelial integrity, reduces microbial translocation, limits inflammation |
TMAO | NF-κB activation; ROS/TXNIP/NLRP3 inflammasome; TGF-β1/Smad3 signaling | ↑ Pro-inflammatory cytokines, ↑ oxidative stress, endothelial dysfunction, fibrosis | Detrimental: promotes atherosclerosis, cardiac dysfunction, and maladaptive remodeling |
Bile Acids (BAs) | FXR activation; AIM2 inflammasome; Type I interferon pathways | Modulation of lipid metabolism, immune responses, mitochondrial dysfunction, cardiac hypertrophy | Detrimental: worsens inflammation, fibrosis, and metabolic derangement |
BCAAs | mTOR pathway activation | ↑ Oxidative stress, ↑ inflammation | Detrimental: exacerbates cardiac stress and injury |
Tryptophan Derivatives (e.g., indole derivatives) | NLRP3 inflammasome modulation; PERK pathway activation | Immune regulation, cellular stress responses | Mixed: potential protective or harmful effects depending on balance |
LPS | TLR4 signaling activation | ↑ Cytokine release, oxidative stress, fibrosis, arrhythmias | Detrimental: drives systemic inflammation and cardiac remodeling |
Metabolite | Activated Pathway | Key Effects | Impact on Hypertension |
---|---|---|---|
Short-Chain Fatty Acids (SCFAs) | GPR43 activation, inhibition of RAS, modulation of ORs (Olfr78, OR10J5) | Vasodilation, reduced inflammation, regulation of sympathetic activity, enhanced NO production | Lowers blood pressure; protective |
Trimethylamine-N-oxide (TMAO) | NF-κB activation, vascular inflammation pathways | Increases vascular inflammation, endothelial dysfunction, platelet hyperresponsiveness | Elevates blood pressure; pro-hypertensive |
Indole Derivatives (from Tryptophan) | Aryl hydrocarbon receptor (AhR) activation | Modulates immune responses, maintains vascular integrity | Generally protective; supports vascular health |
Kynurenine | Immune and vascular modulation | Affects vascular tone and renal function | Variable, depending on pathway balance |
Serotonin (5-HT) | Vascular and renal regulatory pathways | Modulates vascular contraction and renal function | Complex effects; can contribute to hypertension if dysregulated |
Polyamines (Putrescine, Spermidine) | NO synthesis modulation | Regulates vascular tone through NO activation/inhibition | Can lower or raise blood pressure depending on balance |
Lipopolysaccharides (LPS) | TLR4-mediated inflammatory signaling | Induces systemic inflammation, endothelial dysfunction | Promotes hypertension; detrimental |
Metabolite | Activated Pathway | Key Effects | Impact on MI |
---|---|---|---|
Trimethylamine N-oxide (TMAO) | NF-κB activation; calcium signaling disruption; ROS generation | Promotes inflammation, oxidative stress, endothelial dysfunction, arrhythmia, atherosclerotic plaque destabilization | Increases MI risk, worsens myocardial injury and outcomes |
Short-Chain Fatty Acids (SCFAs) (e.g., acetate, butyrate, propionate) | GPR41/43 activation; HDAC inhibition; eNOS activation | Suppress inflammation, improve gut barrier function, enhance vasodilation | Protective role; their reduction may impair MI recovery |
Phenylacetylglutamine (PAGln) | Adrenergic receptor activation on platelets | Enhances platelet aggregation and thrombosis | Elevates thrombotic risk, worsens MI severity |
Lipopolysaccharide (LPS) | TLR4-NF-κB activation; ROS generation | Induces systemic inflammation, oxidative stress, endothelial dysfunction | Exacerbates myocardial injury and adverse remodeling |
Long-Chain Fatty Acids (LCFAs) | Metabolic dysregulation (lipid metabolism) | Promote platelet aggregation and thrombus formation | Potential biomarker for early AMI; contributes to MI initiation |
Aromatic amino acid metabolites | Oxidative stress pathways | Increase ROS generation, influence infarct size | Worsen post-MI outcomes through increased oxidative damage |
Metabolite | Activated Pathway | Key Effects | Impact on Atherosclerosis |
---|---|---|---|
Trimethylamine N-oxide (TMAO) | TMAO pathway, MAPK, NF-κB signaling, inhibition of reverse cholesterol transport |
|
|
Short-Chain Fatty Acids (SCFAs) | PPARγ activation, gut barrier integrity regulation |
|
|
Lipopolysaccharides (LPS) | TLR4 signaling, NF-κB pathway |
|
|
Feature | Healthy Gut Microbiota | Atherosclerosis-Associated Dysbiosis | Hypertension-Associated Dysbiosis | Heart Failure-Associated Dysbiosis | Myocardial Infarction (MI)-Associated Dysbiosis |
---|---|---|---|---|---|
Microbial Diversity | High microbial richness and diversity | Reduced diversity, enrichment of pro-inflammatory species | Lower diversity, increased pathobionts | Significant microbial imbalance, loss of beneficial bacteria | Decreased diversity, dominance of pro-inflammatory bacteria |
Bacillota/Bacteroidota Ratio | Balanced ratio, supporting homeostasis | Increased Bacillota/Bacteroidota ratio (linked to inflammation) | Increased Bacillota, decreased Bacteroidota | Elevated Bacillota levels, disrupting metabolic pathways | Increased Bacillota dominance, linked to inflammation |
SCFA-Producing Bacteria | High levels of Faecalibacterium, Roseburia, Akkermansia | Decreased Faecalibacterium, Roseburia | Reduced Akkermansia muciniphila, impairing gut barrier | Loss of Butyrivibrio and Faecalibacterium | Decreased Roseburia and Akkermansia |
SCFA Levels (Butyrate, Acetate, Propionate) | High, maintaining gut and vascular health | Decreased SCFA levels, leading to endothelial dysfunction | Lower SCFA levels, contributing to vascular stiffness | Markedly reduced SCFAs, worsening systemic inflammation | Reduced SCFAs, promoting pro-thrombotic environment |
Inflammatory Bacteria | Low levels of Escherichia, Enterobacter | Increased Escherichia coli, Enterobacter, Proteobacteria | Overgrowth of Desulfovibrio (H2S producer, causing damage) | Elevated Klebsiella, Enterococcus, Staphylococcus | Increased Enterobacter and Fusobacterium |
LPS-Producing Bacteria | Low levels, preventing endotoxemia | Increased Klebsiella, Parabacteroides | Enrichment of Proteobacteria, elevating systemic LPS | High Enterobacteriaceae, promoting systemic inflammation | Increased Bacteroides and Proteobacteria |
TMAO-Producing Bacteria | Low levels, reducing cardiovascular risk | Enrichment of Lachnoclostridium, Desulfovibrio (TMAO producers) | Increased Clostridia and Fusobacterium, promoting TMAO | Elevated Eggerthella lenta and Desulfovibrio | Increased Lachnospiraceae and Clostridium |
Bile Acid Metabolism | Normal bile acid balance, supporting lipid metabolism | Increased secondary bile acids (pro-inflammatory effects) | Altered bile acid conversion, affecting BP regulation | Elevated toxic bile acids, worsening cardiac function | Disrupted bile acid homeostasis, impairing heart recovery |
Inflammatory Markers | Low levels of IL-6, TNF-α, CRP | Elevated IL-6, TNF-α, CRP, promoting plaque formation | Increased pro-inflammatory cytokines (IL-17, TNF-α) | High IL-6, TNF-α, gut permeability worsens | Increased IL-1β, IL-18, contributing to clot formation |
Endothelial Function | Intact vascular endothelium, healthy BP regulation | Endothelial dysfunction, leading to atherosclerotic plaque | Reduced nitric oxide (NO), causing vascular constriction | Endothelial damage, exacerbating heart failure risk | Vascular inflammation, increasing thrombosis risk |
Gut Barrier Integrity | Strong tight junctions, preventing microbial translocation | Impaired barrier, microbial translocation fuels inflammation | Weakened barrier, increasing BP-related damage | Severe gut leakiness, endotoxemia worsens heart function | Increased permeability, leading to systemic inflammation |
Compound | Sources | Cardioprotective Mechanisms | Key Molecular Targets | Clinical Implications | References |
---|---|---|---|---|---|
Flavonoids | Berries, citrus fruits, onions, tea | Antioxidant, anti-inflammatory, anti-atherosclerotic, anti-thrombotic, improves endothelial function, reduces blood pressure | Nrf2, NF-κB, PI3K-AKT, eNOS, COX-2, NADPH oxidase, MAPK | Potential role in preventing atherosclerosis, hypertension, and MI; needs further clinical translation | [137,138,139,140,141,142,143,144,145,146,147,148,149] |
Omega-3 fatty acids | Fatty fish (EPA, DHA), flaxseeds, walnuts | Reduces triglycerides, lowers blood pressure, is anti-inflammatory, improves endothelial function, stabilizes cardiac electrophysiology | PPAR-α, COX-2, LOX, resolvins, prostacyclin, NO | Beneficial in reducing cardiovascular events, improving lipid profiles, and managing hypertriglyceridemia | [163,164,165,166,167,168,169,170,171,172,173,174] |
Resveratrol | Grapes, peanuts, berries | Antioxidant, anti-inflammatory, anti-atherosclerotic, vasoprotective, inhibits LDL oxidation, enhances NO production | SIRT1, AMPK, estrogen receptor α, NF-κB, eNOS | Potential in managing hypertension, atherosclerosis, and heart failure; concerns regarding bioavailability | [175,176,177,178,179,180,181,182] |
Curcumin | Turmeric, ginger | Reduces oxidative stress, is anti-inflammatory and anti-thrombotic, regulates lipids, inhibits platelet aggregation, prevents atherosclerosis | SIRT1, NF-κB, COX-2, NADPH oxidase | Cardioprotective in conditions like ischemia–reperfusion injury, diabetic cardiomyopathy, and drug-induced toxicity | [183,184,185,186] |
Coenzyme Q10 (CoQ10) | Meat, fish, nuts, spinach, broccoli, whole grains | Antioxidant, mitochondrial function support, reduces oxidative stress, enhances energy production, improves endothelial function | Cytochrome c oxidase, Nrf2, ATP synthase, SIRT1 | Potential benefits in heart failure, ischemic heart disease, hypertension, and statin-induced myopathy | [187,188,189,190,191,192,193] |
Marine-derived compounds | Fish oils, seaweed, marine algae, krill oil | Anti-inflammatory, antioxidant, reduces cholesterol and triglycerides, protects against ischemic damage, improves endothelial health | PPAR-α, SIRT1, eNOS, COX-2, TLR4 | Protective effects in cardiovascular diseases like atherosclerosis, heart failure, and inflammation | [194,195,196,197,198,199,200] |
Natural Product | Gut Microbiota Modulation | Cardiovascular Benefits | Mechanism of Action | References |
---|---|---|---|---|
Berberine | Promotes SCFA-producing bacteria (Roseburia, Blautia, Alistipes) | Reduces cholesterol, triglycerides, and LDL; increases HDL-C | Increases beneficial bacteria, suppresses LPS-induced inflammation via TLR4/NF-κB, improves lipid profiles and strengthens intestinal barrier function | [212,213] |
Polymethoxyflavones (PMFs) | Increases Akkermansia and Bifidobacterium; inhibits TMA-producing bacteria | Prevents vascular inflammation and atherosclerosis; reduces TMAO | Inhibits TMA production, reduces NF-κB/MAPK signaling, improves gut health and prevents atherosclerosis | [214] |
Resveratrol | Promotes Bacteroides, Lactobacillus, Bifidobacterium; reduces Enterococcus faecalis | Lowers risk of atherosclerosis and hypertension; improves endothelial function | Modulates gut microbiota to enhance NO bioavailability, reduces inflammation and oxidative stress, improves bile acid metabolism, and lowers TMAO | [215,216] |
Quercetin | Activates health-promoting bacteria; restores gut microbiota after antibiotic exposure | Anti-obesity, metabolic benefits in metabolic syndrome; reduces inflammation | Strengthens tight junctions, generates antioxidant metabolites, regulates bile acid profiles, blocks inflammasome activation and TLR4 signaling pathway | [217,218,219,220] |
Ferulic Acid (FA) | Increases Lachnospiraceae; reduces Prevotellaceae | Lowers cholesterol, triglycerides, LDL; promotes fat metabolism | Reshapes gut microbiota, activates PPAR-α, inhibits PPAR-β/γ, decreases pro-inflammatory cytokines, and regulates lipid metabolism | [222,223,224] |
Curcumin | Promotes beneficial bacteria; suppresses harmful bacteria | Reduces inflammation and oxidative stress; lowers atherosclerosis risk | Inhibits NF-κB pathway, strengthens intestinal barrier, modulates lipid metabolism, reduces vascular inflammation, and prevents endotoxemia | [226,227] |
Pomegranate Juice | Enhances Bifidobacterium, Lactobacillus, Roseburia, Akkermansia | Reduces atherosclerotic lesions; increases HDL-C and lowers CVD risk | Modulates gut microbiota, reduces atherosclerotic plaque size, enhances NO production, reduces oxidative stress and inflammatory cytokines | [228,229] |
Anthocyanins | Increases Bifidobacterium, Lactobacillus, Roseburia, Akkermansia | Enhances vascular function; reduces plaque formation and aortic inflammation | Enhances NO production, decreases oxidative stress, modulates NF-κB pathway, regulates gene expression linked to atherosclerosis, improves redox homeostasis | [230,231,232,233,234,235] |
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Muttiah, B.; Hanafiah, A. Gut Microbiota and Cardiovascular Diseases: Unraveling the Role of Dysbiosis and Microbial Metabolites. Int. J. Mol. Sci. 2025, 26, 4264. https://doi.org/10.3390/ijms26094264
Muttiah B, Hanafiah A. Gut Microbiota and Cardiovascular Diseases: Unraveling the Role of Dysbiosis and Microbial Metabolites. International Journal of Molecular Sciences. 2025; 26(9):4264. https://doi.org/10.3390/ijms26094264
Chicago/Turabian StyleMuttiah, Barathan, and Alfizah Hanafiah. 2025. "Gut Microbiota and Cardiovascular Diseases: Unraveling the Role of Dysbiosis and Microbial Metabolites" International Journal of Molecular Sciences 26, no. 9: 4264. https://doi.org/10.3390/ijms26094264
APA StyleMuttiah, B., & Hanafiah, A. (2025). Gut Microbiota and Cardiovascular Diseases: Unraveling the Role of Dysbiosis and Microbial Metabolites. International Journal of Molecular Sciences, 26(9), 4264. https://doi.org/10.3390/ijms26094264