Cardiovascular disease (CVD) is one of the major causes of morbidity and mortality throughout the world.1,2 While traditional risk factors are managed intensively, many individuals continue to have considerable residual risk, and emerging factors such as inflammatory mediators are being investigated.1,2 In this light, the gut microbiota is increasingly recognized as a modifiable factor that influences cardiometabolic health.1,2 Recent studies have shown that dysbiosis is linked to various cardiovascular (CV) conditions, suggesting that gut–heart interactions play a role in diseases such as hypertension, diabetes, obesity, atherosclerosis and heart failure (HF).1,3
Aim and objectives
This review aims to explore the role of gut microbiota in CV health and disease. It focuses on elucidating the mechanisms by which microbial metabolites influence CV pathophysiology, examining current evidence on dysbiosis in CVD and evaluating potential microbiome-targeted interventions while highlighting existing knowledge gaps and future research directions.
Gut–heart crosstalk: Rationale and mechanisms
Gut–heart crosstalk refers to the bidirectional communication between the intestinal microbiota and the CV system. Growing evidence connects CV pathophysiology and the gut microbiota.1,3,4 Gut bacteria produce metabolites and immune mediators that can influence host organs, including the heart and blood vessels.3
Importance and knowledge gaps
The gut–heart axis is a major clinically relevant topic because of the enormous burden of CVD and the need for new preventive strategies.1,5 Microbiome studies often report altered gut communities in patients with coronary artery disease and HF, even in the absence of conventional risk factors.5
Nevertheless, there are still important questions. As pointed out in a review, although there are strong links between gut microbes and CVD, it can be difficult to prove direct causation.5 To identify the bacterial taxa or pathways that cause vascular inflammation or myocardial dysfunction and to understand how they interact with host genetics and diet, researchers need to conduct mechanistic research. Methodological problems complicate data interpretation, such as disparities in microbiome sequencing techniques, variations in patient diets and medication regimens, and a lack of standardized measurements. Crucially, the microbiome is not yet included in clinical guidelines for assessing the risk of CVD. We also lack large randomized trials testing whether altering the microbiome can improve hard CV outcomes.
Overview
Gut microbiome composition and diversity
The gut microbiota comprises a group of microorganisms like bacteria, fungi and viruses that reside within the digestive system. Genetics, age, diet, mode of birth and other factors can influence the composition and function. The colonization of the digestive tract begins immediately after birth.6 The composition and diversity of the gut microbiome are unique, much like the host genome. The gene content of these microbiomes (the metagenome) is also considered our alternate genome.7
Although hundreds of species are present, only ~30–40–40 genera account for about 99% of the microbiota’s population.8 Bacteria constitute 60% of the faeces dry mass.6 Firmicutes, Bacteroidetes, Actinobacteria and Proteobacteria are the most dominant bacterial phyla in the human gut, with Bacteroides, Clostridium, Faecalibacterium and Prevotella being the most commonly recorded genera.8
There is a more diverse gut microbiota in people who consume foods containing naturally fermented bacteria (probiotics) and prebiotic fibres, whereas there is a lower gut microbiota diversity in people who use probiotic supplements.9 Breastfed individuals have been shown to develop a more diverse microbiome than those who were formula-fed, and some evidence also suggests that females may have slightly lower diversity than males.9
Microbiome and host metabolism
There are three categories of gut bacteria based on their functions in the host: gut bacteria can be categorized as (1) commensals that are normally harmless, (2) symbionts that are mutually beneficial and (3) pathobionts (or pathogens) that can cause disease under certain conditions.10
Certain Lactobacillus strains have been associated with improvements in cholesterol metabolism and inflammatory responses, which could be beneficial for CV health. They break down bile salts, convert cholesterol into forms that can be excreted without reabsorption and produce beneficial compounds like short-chain fatty acids (SCFAs) that inhibit liver cholesterol production by inhibiting 3-hydroxymethyl-3-glutaryl-CoA reductase enzyme in the liver. SCFAs like butyrate are an energy source for colonic epithelial cells. Some Lactobacillus strains can lower trimethylamine N-oxide (TMAO) levels, reducing inflammation and improving lipid profiles.11
Cyanocobalamin and other endogenous B vitamins are synthesized exclusively by gut microbiota like Firmicutes, Actinobacteria and Proteobacteria strains; these are essential for healthy metabolic processes like DNA replication and repair. Commensal bacteria like Serratia marcescens, Bacteroides fragilis, Enterobacter agglomerans, Eubacterium lentum and Enterococcus faecium also produce vitamin K. Changes in the composition of these bacteria can, therefore, affect the availability of these endogenous vitamins.12
Microbiome and immune system interactions
The microbiota and the immune system are also closely related, and the first two years after birth are important for shaping the gut ecosystem, which helps the immune system to recognize commensal microbes from harmful ones.10 This early microbiome development is significant for long-term immune strength.10 The gut microbiome also undergoes age-related changes in response to the changing environment. To overcome this, the microbiome changes the composition of the bacterial species, as well as the metabolic function.13 The gut lining contains Toll-like receptors that help the immune system to distinguish between friendly commensal bacteria and harmful invaders.13 The decline in immune fitness with ageing breaks the host–microbiome bond, affecting the host’s health and immunity.14 Studies on mice suggest that a balanced gut microbiome might support blood cell production and immunity in older adults.14
The gut microbes also support the production of immunoglobulin A (IgA).13 Bacteria such as B. fragilis, Clostridia and Bifidobacterium infantis promote regulatory T-cell activity, and species like Faecalibacterium prausnitzii decrease pro-inflammatory cytokines like IL-12 and boost anti-inflammatory ones like IL-10, thereby helping reduce inflammation.13
Gut dysbiosis, microbial metabolites and cardiovascular disease mechanisms
Inflammation and endothelial dysfunction
The gut microbiome not only aids in digestion but also impacts health conditions like CVD and many others through its metabolites, such as SCFAs, TMAO and lipopolysaccharides (LPS).15
Current research indicates that gut microbiomes also regulate inflammation by modulating immune cell differentiation, cytokine production and even haematopoiesis (blood cell formation). Chronic inflammation is central to atherosclerosis and contributes to other CVD.16 During dysbiosis, systemic inflammation is triggered by the entry of gut-derived microbial products (particularly LPS from Gram‐negative bacteria) into the circulation.17 LPS activates immune pathways such as TLR4–MYD88–NF-κB, increasing inflammatory cytokines (IL-6, IL-1 and TNF-α) and promoting foam cell formation and cholesterol ester accumulation, thereby contributing to atherosclerosis.17 Elevated LPS from increased gut permeability may also contribute to HF progression.17
People with high blood pressure (BP) tend to have a less diverse gut microbiome, with greater a prevalence of pro-inflammatory genera like Prevotella and Klebsiella.17 For example, Dinakis et al. found that higher plasma butyrate levels were associated with increased arterial stiffness.18 These findings suggest that differences in SCFA levels may be linked to changes in vascular tone and BP in humans.
Endothelial dysfunction is a key early step in CVD pathogenesis, leading to reduced vessel flexibility, inflammation and plaque formation.19 In dysbiosis, increased translocation of microbial products (LPS and other MAMPs) can stimulate endothelial cells, potentially leading to chronic activation and vascular inflammation.18 For instance, TMAO has been implicated in pathways involving NF-κB that may enhance endothelial inflammation and platelet activation, potentially contributing to atherosclerosis.18 Elevated TMAO levels have been associated with a higher risk of heart attack, stroke and CV death.18 Uremic toxins (e.g. indoxyl sulphate or p-cresyl sulphate) from bacterial metabolism of amino acids, hydrogen sulphide (H₂S) from sulphate-reducing bacteria and microbial peptides/quorum-sensing signals can all affect endothelial barrier integrity and drive pathological angiogenesis or inflammation that promotes CVD.20
Lipid metabolism and atherogenesis
The gut microbiome influences lipid metabolism by converting dietary fibre into SCFAs, which regulate energy balance, insulin sensitivity and lipid levels via receptors like GPR41 and GPR43.21 SCFAs also enhance lipid breakdown and reduce circulating triglycerides and cholesterol.21 Bile acids (BAs) are another microbially influenced factor: primary BAs produced in the liver are converted by gut bacteria into secondary BAs that activate receptors (e.g. FXR or TGR5) and thereby influence lipid/glucose metabolism and inflammation. Dysregulated BA profiles can impair lipid handling and worsen cardiometabolic health.18,22 Gut microbes can also convert dietary choline into trimethylamine (TMA), which is oxidized by the liver to TMAO – elevated TMAO levels have been associated with impaired cholesterol transport and may contribute to atherosclerotic processes.18,22 Gut-derived metabolites can influence each step of plaque development. For example, high TMAO impairs reverse cholesterol transport and drives foam cell formation.22 Together, these microbiome-related changes in lipid metabolism may contribute to the development of atherosclerosis.23 Thus, microbial modulation of SCFAs and BAs, as well as microbe-derived metabolites like TMAO, links the gut flora to altered lipid metabolism and plaque progression in CVD. Atherosclerosis occurs due to endothelial injury, followed by lipid buildup and plaque formation. High low-density lipoprotein (LDL), cholesterol, hypertension, diabetes, obesity and inactivity are its major risks. The disease progresses as LDL accumulates and oxidizes within arterial walls, triggering immune cell recruitment, especially monocytes, which become macrophages, which fill up with oxidized low-density lipoprotein (oxLDL) or lipid droplets, forming foam cells, leading to fatty streaks and plaque buildup. These plaques, made up of lipids, inflammatory cells and connective tissue, can narrow arteries and lead to serious CV events like acute coronary syndrome, stroke and HF.23
A randomized controlled trial (RCT) provides evidence that a Mediterranean-style dietary pattern that was rich in fibre and polyphenols led to enhanced microbial gene richness, higher relative abundance of F. prausnitzii and Roseburia hominis, decreased levels of Ruminococcus gnavus and improved metabolic parameters.24 Taken together, these findings provide support for host-diet gut microbiome interactions in modulating inflammation and metabolic regulation. Szabo et al. reported that an increased Firmicutes/Bacteroidetes ratio was linked to greater carotid intima-media thickness (IMT) and arterial stiffness (p=0.031), and Li et al. found that lower F. prausnitzii levels were associated with higher IMT.25,2 Together, these findings suggest that a dysbiosis characterized by a high Firmicutes/Bacteroidetes ratio and low F. prausnitzii is associated with early atherosclerotic changes. Since reduced F. prausnitzii has been associated with carotid IMT, the microbial changes that were observed may provide an important avenue for early atherosclerotic prevention through dietary changes.27
Gut barrier dysfunction and immune system
As described in the section ‘Inflammation and Endothelial Dysfunction’, dysbiosis is linked to increased intestinal permeability, which can allow microbial molecules to enter the bloodstream and trigger systemic inflammation. This activates pro-inflammatory cytokines (IL-6 and TNF-α), which stimulate white blood cell and neutrophil production, as well as liver release of CRP. Those same cytokines further damage the gut barrier, resulting in a vicious cycle of increasing dysbiosis, inflammation and permeability.18 Disruption of the microbial balance can cause immune dysregulation, raising risk for metabolic and inflammatory diseases (diabetes, CVD, IBD, etc.).28 However, when barrier dysfunction is severe, these defenses may be overwhelmed. Studies show that interventions that restore barrier integrity (e.g. certain antibiotics or prebiotics) can reduce circulating LPS and systemic inflammation. Dietary and lifestyle factors also modulate gut integrity: diets rich in fibre (and certain amino acids/vitamins) support barrier health; regular exercise may help maintain gut barrier integrity and is known to improve cardiac health.29
Some experimental studies suggest that faecal microbiota transplantation (FMT) can improve gut barrier function, though its impact on human CVD outcomes remains unproven.30
Microbiota-derived metabolites and cardiovascular disease
The gut microbiome produces a variety of metabolites that are often studied for their potential roles in CV health.
Trimethylamine N-oxide
Gut microbes convert dietary nutrients (e.g. choline or carnitine) into TMA, which is then oxidized in the liver by the enzyme FMO3 to form TMAO.31 A systematic review, which summarized the results of 923 patients with high-risk CV problem, found that higher TMAO levels were associated with increased CV mortality.32 TMAO has been implicated in inflammatory and thrombotic pathways that may contribute to atherogenesis.33
TMAO promotes foam cell formation by increasing cholesterol uptake in macrophages through upregulation of specific receptors, while also reducing BA secretion and reverse cholesterol transport, highlighting its proatherogenic effects.34 A quantitative analysis of plasma TMAO revealed that it contributes to endothelial damage by triggering activation of the NLRP3 inflammasome through cathepsin-B-mediated pathways.35 It downregulates the expression of tight junction proteins of endothelial cells.34 Intestinal dysbiosis may lead to higher TMAO levels, which are associated with cardiac changes (e.g. hypertrophy or fibrosis) that could contribute to HF development.36 High-circulating TMAO has been linked to increased platelet activity and faster clot formation, raising the risk of thrombotic events such as myocardial infarction and stroke.37
Short-chain fatty acids
SCFAs are generated when the gut microbiome ferments dietary fibres and comprise acetate, propionate and butyrate.33 SCFAs can influence cardiometabolic disorders by regulating their risk factors, activating intracellular signalling cascades and interacting with numerous receptors. They can regulate BP and have anti-inflammatory effects, reducing obesity.38
Studies show that butyrate can help reduce obesity by lowering inflammation through its immune effects, while propionate supports weight control by reducing appetite through actions in the brain.39 SCFAs, especially butyrate, help reduce BP by activating specific receptors in blood vessels and kidneys, reduce inflammation through HDAC inhibition and influence nervous system signalling from the gut to the brain.33
SCFAs help maintain gut barrier integrity; if the barrier is compromised, more microbial toxins can enter the circulation, contributing to systemic inflammation and CV risk.40
Some research suggests that SCFAs may influence immune cells (like CX3CR1+ macrophages) involved in cardiac repair, but evidence that SCFAs prevent or treat HF in humans is currently lacking.40 SCFA holds a significant role in maintaining the gut barrier, and through this effect, it alters CVD risks.41
Lipopolysaccharides
When dysbiosis increases gut permeability, LPS can translocate into the circulation and contribute to systemic inflammation.42 Dysbiosis and other factors cause increased intestinal permeability, known as a ‘leaky gut’.43
Studies have shown that gut permeability is increased in individuals with hypertension.33 Its proatherogenic effects include increased receptor expression in foam cells for the uptake of oxLDL.42 The circulation of LPS results in the secretion of inflammatory cytokines, leading to insulin resistance and metabolic disorders.44 Gut permeability-related circulation of LPS helps explore how inflammation contributes to CVDs.29
TMAO and SCFAs have emerged as key microbiota-derived metabolites with significant clinical relevance in CVD. TMAO is a potential indicator and treatment target because of its link to negative CV outcomes. At the same time, SCFAs offer therapeutic potential by modulating inflammation and improving vascular function, which may help reduce hypertension and atherosclerosis risk (though human studies are needed).45,46 LPS may serve as a potential clinical marker to investigate inflammation-driven CVD risk.32 Table 1 summarizes the biomarkers for CVD risk stratification.17,25,26,32–34,37,38,42,47–51
Table 1:Biomarkers for cardiovascular disease risk stratification17,25,26,32–34,37,38,42,47–51
| Biomarker | Microbial source | Associated CVD | Clinical utility | Key refs |
| TMAO | Choline/carnitine-metabolizing bacteria | Atherosclerosis, heart failure and arrhythmia | Risk prediction, therapeutic target | 32–34 |
| SCFAs | Fibre-fermenting bacteria (e.g. F. prausnitzii) | Hypertension and atherosclerosis | Vascular protection marker | 37,38,49 |
| LPS | Gram-negative bacteria | Atherosclerosis and heart failure | Systemic inflammation marker | 17,42 |
| PAGIn | Phenylalanine-metabolizing microbes | Heart failure | Prognostic marker | 50,51 |
| Secondary bile acids | Microbial bile salt hydrolase activity | Dyslipidaemia and atherosclerosis | Metabolic risk indicator | 47,48 |
| F. prausnitzii abundance | Beneficial butyrate producer | Atherosclerosis (protective) | Surrogate of gut health | 25,26 |
CVD = cardiovascular disease; LPS = lipopolysaccharide; PAGln = phenylacetylglutamine; SCFAs = short-chain fatty acids; TMAO = trimethylamine N-oxide.
Gut microbiome and its role in specific cardiovascular disease
Atherosclerosis
The gut microbial metabolites regulate cholesterol metabolism and systemic inflammation and may thereby influence CVD risk.46 BAs act as a ligand to the farnesoid X receptor (FXR), which regulates their production and cholesterol metabolism via cholesterol 7α-hydroxylase (CYP7A1) and small heterodimer partner (SHP) pathways.47 The gut microbiome deconjugates from primary BA to secondary BA using biliary salt hydrolase (BSH).48 During dysbiosis, BSH is reduced, causing BA reabsorption and redundant FXR activation. This results in repression of CYP7A1 and downregulation of ATP-binding cassette transporters (ABCG5/ABCG8), thereby reducing cholesterol excretion. Hence, dysbiosis and altered BA metabolism may disturb cholesterol homeostasis and contribute to elevated cholesterol levels, a major risk factor for atherosclerosis.52
A prospective cohort study by Haghikia et al. on 671 patients with previous ischaemic stroke revealed the relationship between increased TMAO levels and the risk of CV events in life.52 The higher TMAO levels have been shown to impair reverse cholesterol transport and promote foam cell formation and inflammation. These changes could create a feedback loop that accelerates atherosclerotic plaque development.52,53 Similarly, the effects of plasma TMAO levels on new atherosclerosis and plaque rupture in patients with highly late stent thrombosis were observed in a study conducted by Tan et al.54
Hypertension
Gut-derived metabolites can influence immune function and metabolism and may also affect BP regulation.55 SCFAs produced by gut microbes influence BP after reaching the bloodstream, where they interact with G-protein-coupled receptors (GPR41 and GPR43) and Olfr78 in the kidneys and blood vessels.56 The activation of Olfr78 has been shown to increase renin release and raise BP, whereas the activation of GPR41 and GPR43 causes vasodilation and lowers BP.57 Hence, the ultimate effect is based on the relative activation of these receptors by SCFAs. The SCFA availability decreases with dysbiosis and thus influences these signalling pathways, promoting pro-hypertensive states.49 Butyrate improves endothelial function and reduces oxidative stress, thereby attenuating angiotensin-II-induced hypertension. Even acetate and propionate impact BP through interaction with the renin-angiotensin system.49
A cross-sectional study by Zhou et al. shows the association of SCFA and BP.58 The acetate (odds ratio=0.696) and valerate (odds ratio=0.713) had a negative correlation with hypertension in their multiple logistic regression analysis.58 In linear regression, acetate (with a regression coefficient=-3.89) and systolic BP had a significant negative association.58 These results suggest a new therapeutic approach using SCFAs in patients with hypertension.
Heart failure
HF is a major problem across the world, causing morbidity and mortality in affected individuals.59 The disrupted gut barrier marks the point of translocation of microbial components into the circulation, and it promotes a state of chronic inflammation.60 LPS in circulation activates TLR4 signalling, initiating endothelial dysfunction and triggering pro-inflammatory cytokine release, which ultimately worsens cardiac remodelling and HF progression.61
A recent study by Zhang et al. identified phenylacetylglutamine (PAGln, a gut-derived phenylalanine metabolite) as a potential contributor to HF.50 The higher values of serum PAGln were found in patients with higher New York Heart Association (NYHA) classification compared with those with milder cases.50 The median PAGln value corresponds to 104.0 ng/mL and 186.7 ng/mL, respectively, for NYHA Class III and IV.50 Romano et al. have also demonstrated the contribution of PAGln in adverse cardiac events and myocardial stress via adrenergic receptor signalling.51
Arrhythmia
Arrhythmia is an abnormal heart rhythm (irregular, fast, slow or missed beats). Atrial fibrillation (AF), characterized by rapid, disorganized atrial contractions, arises from structural/electrical atrial remodelling. Dysbiosis has been associated with higher levels of metabolites (e.g. TMAO) and lower SCFAs, which could contribute to biochemical changes involved in atrial remodelling.62 A cohort study by Svingan et al. clearly indicated the involvement of TMAO in AF.63 The study of 3,797 patients whose TMAO levels were increased had a significant risk of incidence of AF with a hazard ratio of 1.12 per 1-standard deviation (SD) increase.63
The electrical remodelling includes shortened action potential duration, a decrease in L-type calcium channel gene expression and altered potassium currents. Structural changes include myocardial fibrosis and atrial dilatation. Taken together, these electrophysiological and structural changes promote sustained arrhythmic activity.63 Elevated TMAO has been linked to the activation of pathways (TGF-β/NLRP3) that may promote myocardial fibrosis.64 Thus, microbial metabolites may influence atrial electrophysiology and structure in ways that could increase AF risk. Table 2 summarizes the microbiome and CVD associations.17,22,25,26,49–51,56,57,60–64
Table 2:Microbiome and cardiovascular disease associations17,22,25,26,49–51,56,57,60–64
| Condition | Microbial changes | Key metabolites | Mechanisms | Key refs |
| Atherosclerosis | ↑ Firmicutes/Bacteroidetes, ↓ F. prausnitzii | TMAO, LPS and dysregulated SCFAs | Inflammation, impaired lipid metabolism and endothelial dysfunction | 17,22,25,26 |
| Hypertension | ↓ SCFA producers, ↑ Prevotella and Klebsiella | Reduced SCFAs and LPS | Altered GPCR/Olfr78 signalling and systemic inflammation | 17,49,56,57 |
| Heart failure | Barrier dysfunction and dysbiosis | TMAO, PAGln and LPS | Chronic inflammation and cardiac remodelling | 50,51,60,61 |
| Arrhythmia | Dysbiosis with high TMAO and low SCFA | TMAO | Fibrosis via TGF-β/NLRP3 and electrical remodelling | 62–64 |
GPCR = G-Protein-Coupled Receptor; LPS = lipopolysaccharide; PAGln = phenylacetylglutamine; SCFAs = short-chain fatty acids; TGF-NLRP3 = Transforming Growth Factor–NOD-like receptor protein 3 inflammasome; TMAO = trimethylamine N-oxide.
Therapeutic modulation of gut microbiome
Diet and lifestyle
Dietary modification offers a low-risk approach to modulating the gut microbiome and influencing CV risk, though responses vary among individuals.66.67 Adherence to a Mediterranean or high-fibre diet is linked to a gut microbiome enriched in SCFA-producing bacteria and reduced CVD risk.65,66 Large trials and meta-analyses confirm the CV benefits of the Mediterranean diet (MD).65,67 In Prevención con Dieta Mediterránea (PREDIMED), high-risk adults following an MD supplemented with olive oil or nuts experienced fewer major CV events than those on a low-fat diet.66 Systematic reviews similarly associate higher MD adherence with lower risks of coronary heart disease, stroke and HF, despite some heterogeneity.65,67
Part of the MD’s benefit stems from its anti-inflammatory and endothelial-protective effects. It reduces vascular inflammation and improves endothelial function, which may contribute to reduced HF risk, though causality remains uncertain.65 Rich in plant polyphenols from sources like fruits, vegetables, tea and wine, the MD promotes microbial metabolism of these compounds into bioactive, anti-inflammatory metabolites.67,68
In summary, multiple trials have shown that diets such as the MD, high in fibre, unsaturated fats and polyphenols are linked to healthier gut microbes (more SCFA producers) and lower CVD risk.65,66 However, we should avoid implying direct causation (for example, it is incorrect to say the MD directly prevents HF). Instead, it is accurate to say that MD-like diets reduce inflammation and improve vascular function, which may help prevent HF over time. Overall, dietary change is a safe strategy to modulate the microbiome, but more research is needed to predict individual responses and identify optimal diets for heart health.
Probiotics, prebiotics and synbiotics
Definitions: Probiotics are live microorganisms (usually bacteria) given as supplements or in foods to confer a health benefit. Prebiotics are non-digestible fibres or substrates (like inulin) that selectively feed beneficial gut microbes. Synbiotics are combinations of probiotics and prebiotics designed to synergize.
Probiotics: Several clinical trials have tested probiotics (various strains and doses) for CV risk factors. Meta-analyses indicate that any benefits on BP or lipids are generally small.69 For example, a recent pooled analysis of 26 randomized trials (1,624 subjects) found that long-term probiotic use lowered office systolic BP by only ~2.2 mmHg and diastolic BP by ~1.1 mmHg on average.69 Similarly, umbrella reviews report that probiotics yield minor reductions in total cholesterol and LDL-C.69 Some trials in patients with hypertension or metabolic disease show slightly larger effects, but results vary by strain and duration. Probiotics also modestly reduce systemic inflammation: one meta-analysis found significant decreases in markers like hs-CRP, TNF-α and IL-6 after supplementation.70
Evidence summary: Overall, probiotic supplements can lead to modest improvements in BP, blood lipids and inflammatory markers.69–71 However, effects differ by specific strains and doses, and many studies are short-term or small. Importantly, no probiotic supplement has been proven to reduce actual CVD events. Safety and standardization are also concerns, as probiotic products vary widely.
Prebiotics: Prebiotics such as inulin, pectins or galacto-oligosaccharides escape digestion and are fermented by the gut microbiota into SCFAs (acetate, propionate and butyrate).72,73 These SCFAs have direct vascular benefits: for example, experimental studies show that acetate and butyrate boost endothelial nitric oxide and lower oxidative stress.72 In animal models, adding inulin to a high-fat diet reduced LDL cholesterol, systemic endotoxin, arterial inflammation and plaque formation.74 In that study, atherosclerotic mice on inulin had lower blood lipids, reduced aortic plaque area and less vascular inflammation compared to controls.74 Human trials of prebiotics are fewer and often short-term, but some report modest improvements in glucose metabolism or inflammation (likely via increased SCFAs).75,76
Evidence summary: Compounds like inulin consistently ferment to SCFAs that support endothelial health.72 In preclinical models, inulin and other fibres attenuate inflammation and atherosclerosis.74 In humans, most prebiotic studies are small; they suggest possible benefits on metabolic markers (e.g. glucose or insulin), but clinical data on CV outcomes are lacking. Thus, while prebiotic fibres could biologically improve CV risk factors via SCFA production, definitive evidence in patients is still limited.
Synbiotics: Synbiotics combine both a probiotic organism and a prebiotic fibre. Preclinical work suggests potential synergy, but human data are still emerging. Some small trials have used synbiotic formulas (e.g. a Lactobacillus strain plus fructo-oligosaccharide) and reported small improvements in lipids or inflammation.76 An umbrella meta-analysis found that synbiotic supplements yield statistically significant but quantitatively small decreases in BMI and lipids (LDL-C, total cholesterol and triglycerides).76 For instance, synbiotics use lowered LDL by only ~2–3–3 mg/dL on average.76
Evidence summary: Overall, synbiotics may slightly improve surrogate risk factors. Meta-analyses suggest minor drops in weight, BMI and LDL-C.76 However, no studies have shown reductions in cardiovascular events. Human trials vary widely in strains and dosages, so it is hard to draw firm conclusions. Given this, it is critical to emphasize that no probiotic or synbiotic product is proven to prevent heart attacks or strokes; they are not a substitute for established therapies. Safety and regulatory issues (e.g. identifying effective strains and doses) remain challenges.69,71 In practice, reported benefits of probiotics/prebiotics/synbiotics on CVD are indirect and modest (e.g. ‘some trials report small improvements in BP, lipids or inflammatory markers’ rather than direct disease prevention).69,71
Faecal microbiota transplantation and other experimental therapies
FMT involves transferring stool (and its microbes) from a healthy donor into a patient’s gastrointestinal tract, typically by colonoscopy, enema or capsules. It has proven effective for Clostridioides difficile infection, so researchers are testing it for metabolic and CV conditions.77 FMT procedures are complex (donor screening and stool processing), but we can summarize key findings relevant to CVD.77
In hypertension, one recent trial (Fan et al., 2025) administered oral FMT capsules to adults with high BP.78 After 1 week, systolic BP fell by an average of 4.3 mmHg in the FMT group compared to placebo. However, this effect was transient and did not persist after continued treatment. Notably, safety was acceptable. These results suggest a possible microbiome-driven BP effect, but it was modest and short-lived.78 In other words, FMT for hypertension remains experimental: it is not a standard therapy, and longer-term benefits have not been demonstrated.
Animal studies provide proof-of-concept: for example, Kim et al. showed that transplanting gut microbiota from genetically atherosclerosis-resistant mice into atherosclerosis-prone mice reduced plaque formation.79 Conversely, giving diseased mice a ‘bad’ microbiome worsened their plaque burden.79 These mouse studies imply that FMT can influence atherosclerosis development, but clear human data are lacking. In summary, FMT has been shown to modulate hypertension and atherosclerosis in preliminary settings.78,79
Other experimental approaches: Beyond FMT, researchers are exploring diverse gut-targeted interventions:
-
TMAO/TMA inhibitors: Inhibiting the gut production of TMA, which is converted to pro-atherogenic TMAO, is under study. A prototype inhibitor, 3,3-dimethyl-1-butanol (DMB), has been shown in mice to suppress TMAO formation and prevent age-related vascular stiffening.80 For example, long-term DMB supplementation in mice normalized endothelial function and reduced arterial stiffness by lowering TMAO.80 These findings suggest a potential way to reduce vascular dysfunction via the microbiome, but human trials are needed.
-
Engineered probiotics: Researchers are developing bacteria that can either consume TMA or generate beneficial metabolites. For example, engineered strains might be designed to break down choline/TMA before it converts to TMAO or to produce compounds that protect blood vessels. These methods are still primarily in the research phase and have not yet been tested in clinical settings.81
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Selective antibiotics: By targeting specific microbial groups with narrow-spectrum antibiotics, there is potential to alter metabolism. However, the widespread use of broad-spectrum antibiotics disrupts gut ecology and may lead to negative outcomes. Currently, no antibiotic treatment has demonstrated an improvement in CVD outcomes, making this approach largely theoretical.82
All of these interventions encounter a significant challenge: interindividual variability in the microbiome. The same therapy may yield different results across individuals based on their unique gut flora. Consequently, personalized responses are expected, complicating predictions about who will benefit. Currently, FMT and other gut-targeted therapies represent promising research opportunities, but they are not established treatments for CVD. Future studies will need to determine which patients, if any, may experience clinical benefits from these innovative strategies.78,79 Table 3 summarizes therapeutic interventions and their effects.65–69,71–79,81
Table 3:Therapeutic interventions and their effects65–69,71–79,81
| Intervention | Mechanism of action | Documented CV effects | Clinical status | Key refs |
| Mediterranean diet | Enriches SCFA producers and polyphenol metabolism | ↓ Major CV events in PREDIMED | Guideline-recommended | 65–67 |
| Probiotics | Introduce beneficial strains and modest BP/lipid improvements | −2/−1 mmHg BP reduction and ↓ LDL | Marketed supplements | 68,69,71 |
| Prebiotics (e.g. inulin) | Fermented to SCFAs and anti-inflammatory | Improved endothelial NO and ↓ plaque in mice | Food additive/ supplement | 72–74 |
| Synbiotics | Synergy of probiotic + prebiotic | Small reductions in BMI and LDL | Emerging | 75,76 |
| Faecal microbiota transplantation | Whole-microbiome replacement | Transient BP drop and experimental | Clinical trials | 77,78 |
| TMAO inhibitors (e.g. DMB) | Block TMA formation | Prevented arterial stiffening in mice | Preclinical | 79 |
| Engineered probiotics | Produce SCFAs/degrade TMA | Protected myocardium in animal models | Preclinical | 81 |
BMI = body mass index; BP = blood pressure; CV = cardiovascular; DMB = 3,3-dimethyl-1-butanol; LDL = low-density lipoprotein; NO = nitric oxide; PREDIMED = Prevención con Dieta Mediterránea; SCFAs = short-chain fatty acids; TMA = trimethylamine; TMAO = trimethylamine N-oxide.
Challenges and limitations
Microbiome research faces major challenges due to extreme interpersonal variability influenced by ethnicity, diet, age and geography.83,84 Breastfeeding rates and the timing and introduction of solid foods in childhood are associated with this variability.85 Due to biological diversity, it is difficult to establish universal microbial markers or a ‘healthy’ baseline.83 Another key barrier is standardization, as variations in DNA extraction procedures, sequencing platforms and analytical pipelines generate technical artefacts that reduce reproducibility.84,86 Even in well-controlled feeding studies, standardized diets diminish intra-individual variances but do not eradicate inter-personal microbiome disparities.87 Moreover, the existing reference databases, which are used in this field, remain incomplete, with many microbial species poorly characterized.88 Current microbiome analysis methods have significant technical limitations. Widely used 16S rRNA sequencing has low taxonomic resolution and generates platform-specific biases.89 Much current research focuses primarily on bacteria, while overlooking ‘The Dark Matter’ of the gut, including viruses, fungi and archaea, which play major roles in microbiome activity.90 While these methodological gaps limit precise characterization of microbial communities, equally significant challenges arise when attempting to translate findings into biologically relevant models. Standard laboratory mouse models have microbiomes that differ markedly from humans.91 Variations in animal supplier, diet formulation and housing circumstances create confounding variables, limiting the clinical applicability of preclinical findings.91 These methodological limitations present considerable challenges to obtaining therapeutically useful knowledge. Despite numerous associations, demonstrating causality between gut microbiota and CVD has been difficult due to the complex interplay of host and environmental factors.92 While numerous studies find links between microbial profiles and disease states, few show clear causal correlations. Most human studies are cross-sectional or observational, so causality cannot be inferred.93 Longitudinal, interventional designs are needed to assess cause-and-effect. Clinical heterogeneity (e.g. differences in diet, concomitant medications like statins or proton pump inhibitors and comorbidities) further confounds gut–heart microbiome studies.92 Moreover, different studies often report different microbial ‘signatures’ for the same disease, reflecting small sample sizes and methodological differences.94 In addition, most studies focus on high-income (Western) populations; underrepresentation of other ethnic and lifestyle groups limits the global applicability of findings.95 Even clinical translation of therapies remains challenging; for example, regulatory and ethical frameworks for interventions like FMT are still evolving.96 This gap persists because host–microbe interactions and environmental influences are incredibly complex. Large-scale projects such as the Human Microbiome Project have made advances towards standardization, but the field still lacks comprehensive reference datasets and analytical frameworks. Without addressing these fundamental concerns, the translation of microbiome research into clinical and therapeutic implications will be limited by reproducibility issues and poor mechanistic knowledge. Addressing these challenges will require coordinated efforts (e.g. standardized protocols and data sharing) to improve reproducibility and build robust reference datasets.94
Future directions
The integration of multi-omics methods such as metagenomics, metatranscriptomics, metaproteomics and metabolomics is transforming our understanding of the gut microbiome’s role in CVD. These technologies enable researchers to examine microbial diversity, gene expression, protein function and metabolic activity, resulting in a comprehensive understanding of host–microbiome interactions.97 For example, metagenomics aids in the identification of microbial species associated with atherosclerosis, whereas metabolomics identifies important compounds such as TMAO and SCFAs that influence heart health.98 Combining metagenomic sequencing with metabolomics can link specific microbial genes to bioactive compounds (like TMAO or SCFAs) and thus to CVD phenotypes, moving beyond simple association.99 Future studies should integrate multi-omics data with systems biology to decode microbial networks and their mechanistic links to CVDs. Tools like high-throughput sequencing and bioinformatics will play a key role in uncovering these microbial pathways. Furthermore, microfluidic organ-on-a-chip and gut-simulation models (for example, linking a gut-on-chip to a vascular tissue model) could allow testing of gut–heart interactions in vitro and reduce reliance on animal models.100 Gut microbiome-derived biomarkers (e.g. TMAO, SCFAs and LPS) are promising candidates for CVD risk assessment. Elevated TMAO levels, for example, are associated with atherosclerosis and HF risk, making it a potential diagnostic marker (pending further validation).101 Similarly, patients with low levels of important beneficial bacteria such as Faecalibacterium and Roseburia tend to have inflammation and high BP. These microbial signatures could help doctors assess patient risk more precisely.102 Future work should validate these markers in large, diverse cohorts and develop standardized assays for clinical use.103 Researchers should also explore novel biomarkers, such as circulating bacterial DNA in blood, which is being investigated as a potential indicator of gut barrier disruption in CVD.104
Artificial intelligence (AI) and machine learning are advancing microbiome research by enabling personalized analysis of complex data. For example, AI models can analyse large multi-omic datasets to identify microbial patterns predictive of CVD risk or to recommend targeted interventions.105 Machine learning might predict which patients will benefit most from high-fibre diets (to boost SCFAs) or specific probiotics to reduce inflammation. However, these models require large, high-quality datasets and careful validation to avoid bias. Ethical considerations like data privacy and algorithmic bias must also be addressed to ensure equitable, reliable results.106
Well-designed clinical trials will be critical to translate these findings. Future studies should include RCTs of gut-targeted interventions (dietary changes, prebiotics or probiotics) with hard cardiovascular endpoints in diverse populations.107 Mechanistic trials in humans (e.g. microbial transplantation or use of labelled substrates to trace microbe–host metabolism) will help establish causality between specific bacteria and host physiology.108
While these directions are promising, it is important to balance optimism with rigour. Integrating multi-omics, AI and novel model systems could lead to a deeper understanding of how gut microbes affect heart health and to personalized microbiome-based therapies. Achieving this will require interdisciplinary collaboration and robust methods, ensuring advances benefit all populations equally.109 Table 4 summarizes the future directions and research prioirities.97–99,101–104,107
Table 4:Future directions and research priorities97–99,101–104,107
| Priority area | Rationale | Expected impact | Key refs |
| Multi-omics integration | Link genes→metabolites→phenotype | Mechanistic insights | 97,98 |
| Biomarker validation | Standardize TMAO and SCFA assays | Risk stratification | 101,102 |
| AI applications | Predict responders and personalize diet | Precision medicine | 103,104 |
| Novel model systems | Gut-heart-on-chip | Reduce animal use | 99 |
| Large RCTs of microbiome therapies | Test hard CV endpoints | Evidence-based practice | 107 |
AI = Artificial Intelligence; CV = cardiovascular; RCT = randomized controlled trails; SCFA = short-chain fatty acid; TMAO = trimethylamine N-oxide.
Conclusion
CVD continues to pose a significant global health burden, with residual risks persisting despite advances in conventional preventive and therapeutic strategies. Growing evidence highlights the gut microbiota as a critical, yet underexplored, factor influencing cardiovascular health through a complex interplay of metabolic, immune and inflammatory mechanisms. Key microbial metabolites such as TMAO, SCFAs, BAs and LPS have emerged as important modulators of endothelial function, lipid metabolism and systemic inflammation, directly impacting the development and progression of atherosclerosis, hypertension, HF and arrhythmias.
The findings reviewed here underscore the therapeutic potential of microbiome-targeted interventions, including dietary modifications such as the Mediterranean and high-fibre diets, probiotics, prebiotics, synbiotics and emerging strategies like FMT. While small-scale studies report modest improvements in CV risk markers such as reduced BP, improved lipid profiles and decreased inflammatory responses, there remains a lack of robust, large-scale RCTs confirming their impact on major CV outcomes. This gap reflects the complexity of microbiome research, marked by inter-individual variability, methodological limitations and challenges in establishing causality.
Future directions should prioritize the integration of multi-omics approaches, biomarker validation and artificial intelligence to decode the gut–heart axis and enable precision-based therapeutic strategies. Translating microbiome science into clinical practice requires rigorous longitudinal studies, standardized methodologies and diverse population studies. Ultimately, understanding and modulating the gut microbiota offers a promising frontier to complement traditional CVD management, potentially leading to innovative and personalized preventive and therapeutic interventions.
