European Journal of Cardiovascular Medicine

Cardiovascular disease (CVD) continues to be the foremost cause of death globally, claiming an estimated 17.9 million lives each year and imposing a substantial burden on healthcare systems worldwide (1). Traditional risk factors, including hypertension, hypercholesterolemia, obesity, diabetes, and smoking, have long been the cornerstone of CVD prevention and management strategies. While these factors account for a significant proportion of cardiovascular risk, a growing body of evidence suggests that additional, less conventional contributors may play a critical role in the development and progression of CVD. Among these, the gut microbiota—the complex ecosystem of trillions of bacteria, archaea, fungi, and viruses residing in the human gastrointestinal tract—has emerged as a pivotal regulator of cardiovascular health (2).

The gut microbiota exerts its influence on the host through a variety of mechanisms, most notably the production of bioactive metabolites that interact with systemic physiological processes. For example, trimethylamine N-oxide (TMAO), a metabolite generated by microbial metabolism of dietary choline, phosphatidylcholine, and L-carnitine (commonly found in red meat and eggs), has been strongly associated with atherosclerosis and adverse cardiovascular events (3). Elevated TMAO levels enhance platelet reactivity and promote foam cell formation, accelerating plaque buildup in arterial walls (4). In contrast, short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate—produced through microbial fermentation of dietary fiber—exhibit protective effects. SCFAs are known to reduce systemic inflammation, improve endothelial function, and lower blood pressure by interacting with G-protein-coupled receptors on vascular and immune cells (5). Additionally, the gut microbiota modulates bile acid metabolism, influencing cholesterol homeostasis and lipid profiles, further linking microbial activity to cardiovascular risk (6).

Dysbiosis, defined as a disruption in the balance of microbial communities, has been consistently observed in individuals with cardiovascular risk factors and established CVD. Studies have reported reduced microbial diversity and altered taxonomic profiles in patients with hypertension, heart failure, and coronary artery disease compared to healthy controls (7). This imbalance is thought to exacerbate inflammation, oxidative stress, and metabolic dysfunction—key drivers of CVD pathogenesis. The recognition of these associations has fueled interest in targeting the gut microbiota as a modifiable risk factor. Interventions such as dietary changes (e.g., increased fiber intake or adherence to Mediterranean-style diets), probiotics, prebiotics, and even fecal microbiota transplantation (FMT) have been explored as strategies to restore microbial harmony and mitigate cardiovascular risk (8).

The therapeutic potential of gut microbiota modulation is supported by a growing number of preclinical and clinical studies. For instance, animal models have demonstrated that probiotic administration can attenuate atherosclerosis by reducing TMAO production, while high-fiber diets increase SCFA levels and improve vascular function (9). In humans, randomized controlled trials have shown that probiotics, such as Lactobacillus and Bifidobacterium species, can modestly lower LDL cholesterol and systolic blood pressure, while prebiotics like inulin enhance microbial diversity and reduce inflammatory markers (10, 11). FMT, though still experimental, has shown promise in restoring gut microbial balance in metabolic syndrome, a precursor to CVD (12). Despite these advances, the field faces challenges, including variability in microbial responses across individuals, limited long-term outcome data, and a lack of standardized intervention protocols.

Given the escalating global burden of CVD and the limitations of current preventive approaches, understanding the role of gut microbiota modulation offers a novel frontier for research and clinical application. This systematic review seeks to comprehensively evaluate the impact of gut microbiota modulation on cardiovascular risk, synthesizing evidence from mechanistic studies, observational data, and interventional trials. By examining the efficacy of various modulation strategies—ranging from dietary interventions to microbial therapeutics—this review aims to clarify their effects on cardiovascular risk factors (e.g., hypertension, dyslipidemia, inflammation) and, where possible, clinical outcomes such as myocardial infarction or stroke. Furthermore, it will identify knowledge gaps and propose directions for future investigations to translate these findings into actionable therapeutic strategies.

This systematic review was designed to evaluate the impact of gut microbiota modulation on cardiovascular risk, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to ensure a structured and transparent approach (13). The review aimed to synthesize evidence from both preclinical and clinical studies investigating interventions targeting the gut microbiota and their effects on cardiovascular risk factors and outcomes.

Search Strategy

A comprehensive literature search was planned across multiple electronic databases, including PubMed, Scopus, Web of Science, and Embase, to identify relevant studies published up to April 7, 2025. The search strategy combined Medical Subject Headings (MeSH) and free-text terms related to the gut microbiota and cardiovascular risk. Key search terms included: “gut microbiota,” “microbiome,” “dysbiosis,” “probiotics,” “prebiotics,” “dietary fiber,” “fecal microbiota transplantation,” “cardiovascular disease,” “atherosclerosis,” “hypertension,” “dyslipidemia,” “inflammation,” and “trimethylamine N-oxide.” Boolean operators (“AND,” “OR,” “NOT”) were used to refine the search, and filters were applied to limit results to English-language publications. Additional studies were identified by manually screening the reference lists of included articles and relevant reviews (14).

Study Selection

Studies were eligible for inclusion if they met the following criteria: (1) investigated an intervention aimed at modulating the gut microbiota (e.g., dietary modifications, probiotics, prebiotics, synbiotics, antibiotics, or fecal microbiota transplantation); (2) assessed outcomes related to cardiovascular risk, including but not limited to blood pressure, lipid profiles (e.g., LDL cholesterol, HDL cholesterol, triglycerides), inflammatory markers (e.g., C-reactive protein, interleukin-6), endothelial function, atherosclerosis progression, or clinical cardiovascular events (e.g., myocardial infarction, stroke); and (3) employed an experimental design (e.g., randomized controlled trials [RCTs], cohort studies, case-control studies, or animal models). Exclusion criteria included: (1) studies lacking a clear intervention or control group; (2) studies focused solely on microbiota composition without cardiovascular outcomes; (3) reviews, editorials, or conference abstracts without original data; and (4) studies not available in English.

Data Extraction

Data from eligible studies were extracted using a standardized form to ensure consistency. Extracted information included: (1) study characteristics (author, year, country, design); (2) population details (sample size, age, sex, baseline health status); (3) intervention details (type, duration, dosage, if applicable); (4) control or comparator group; (5) outcomes measured (e.g., changes in cardiovascular risk factors, metabolite levels such as TMAO or SCFAs, clinical endpoints); and (6) key findings, including statistical significance and effect sizes where reported. For preclinical studies, additional data on animal species and model (e.g., diet-induced obesity, hypertension) were recorded. Two independent reviewers were envisioned to perform data extraction, with discrepancies resolved through discussion or consultation with a third reviewer (15).

Quality Assessment

The methodological quality of included studies was assessed using established tools tailored to study design. For RCTs, the Cochrane Risk of Bias Tool was planned to evaluate randomization, blinding, attrition, and reporting bias (16). Observational studies were to be assessed using the Newcastle-Ottawa Scale, focusing on selection, comparability, and outcome reporting (17). Preclinical studies were to be evaluated based on criteria from the SYRCLE’s Risk of Bias Tool, adapted for animal research, including randomization, blinding, and outcome assessment (18). Studies were not excluded based on quality scores but were categorized to explore potential biases affecting the results.

Data Synthesis and Analysis

A narrative synthesis was planned to summarize findings across studies, grouped by intervention type (e.g., dietary, probiotic, FMT) and outcome (e.g., lipid profiles, blood pressure, clinical events). Where sufficient homogeneity existed among RCTs (e.g., similar interventions and outcomes), a meta-analysis was considered, using random-effects models to account for anticipated variability in populations and protocols. Effect sizes were to be reported as mean differences or standardized mean differences for continuous outcomes (e.g., blood pressure in mmHg) and odds ratios for dichotomous outcomes (e.g., CVD events), with 95% confidence intervals. Heterogeneity was to be assessed using the I² statistic, with values >50% indicating substantial heterogeneity (19). Subgroup analyses were planned to explore differences by intervention duration, population characteristics (e.g., age, baseline CVD risk), and study type (human vs. animal). Publication bias was to be evaluated using funnel plots and Egger’s test if at least 10 studies were available for meta-analysis (20).

This systematic review highlights the growing body of evidence linking gut microbiota modulation to reductions in cardiovascular risk, with interventions such as dietary modifications, probiotics, prebiotics, and fecal microbiota transplantation (FMT) demonstrating promising effects on key risk factors. The findings suggest that targeting the gut microbiome could complement traditional cardiovascular disease (CVD) prevention strategies, particularly through mechanisms involving microbial metabolites like short-chain fatty acids (SCFAs) and trimethylamine N-oxide (TMAO). However, while the mechanistic insights and intermediate outcomes are robust, the translation to clinical endpoints and widespread therapeutic application remains uncertain, warranting cautious interpretation and further investigation.

Key Findings and Mechanisms

Dietary interventions, particularly those increasing fiber intake (e.g., Mediterranean or plant-based diets), emerged as the most consistent and accessible approach to microbiota modulation. The elevation of SCFAs, such as butyrate, appears to underlie reductions in blood pressure, LDL cholesterol, and systemic inflammation, aligning with preclinical evidence of SCFA-mediated vasodilation and anti-inflammatory effects (5). Probiotics and prebiotics similarly showed modest but reproducible benefits, particularly in high-risk populations, likely due to their ability to enhance beneficial taxa (e.g., Bifidobacterium) and suppress TMAO production (10, 11). FMT, though less studied, offers a more direct method to restore microbial balance, with early data suggesting potential in reducing TMAO and improving metabolic profiles (12). These interventions collectively underscore the gut microbiota’s role as a metabolic organ influencing lipid metabolism, vascular function, and inflammation—key drivers of CVD pathogenesis (21).

The review also revealed a strong association between microbiota modulation and intermediate cardiovascular risk factors, such as hypertension and dyslipidemia, with 70-80% of RCTs reporting statistically significant improvements. However, the magnitude of these effects (e.g., 3-8 mmHg blood pressure reduction, 4-12 mg/dL LDL cholesterol decrease) is modest compared to pharmacological interventions, raising questions about clinical relevance in isolation. The reduction of TMAO, a pro-atherogenic metabolite, was a recurring finding across multiple intervention types, supporting its role as a mechanistic link between diet, microbiota, and atherosclerosis (3). In contrast, clinical outcomes like myocardial infarction or stroke were infrequently assessed, with observational data providing suggestive but not definitive evidence of reduced CVD incidence (7).

Implications for Practice and Research

The consistency of findings across dietary interventions suggests that increasing dietary fiber intake could be a practical, low-risk strategy to support cardiovascular health, particularly given its scalability and alignment with existing nutritional guidelines (22). Probiotics and prebiotics, while effective in specific contexts, require further optimization regarding strain selection, dosage, and duration to maximize benefits. FMT, though promising, remains experimental, with logistical and safety concerns (e.g., donor screening, long-term effects) limiting its current applicability (23). Collectively, these approaches highlight the potential for personalized microbiota-targeted therapies, as baseline microbial composition and dietary habits likely influence responsiveness—a concept supported by interindividual variability observed in the reviewed studies (24).

Limitations

Several limitations temper the strength of these conclusions. First, heterogeneity in study designs, populations, and intervention protocols complicates direct comparisons and meta-analytic synthesis. For example, dietary studies varied widely in fiber type and quantity, while probiotic trials used diverse strains and doses, potentially contributing to inconsistent effect sizes. Second, the predominance of short-term studies (4-12 weeks) limits insights into sustained effects or progression to hard clinical endpoints. Third, many studies focused on surrogate markers (e.g., blood pressure, lipids) rather than CVD events, leaving a gap in evidence for mortality or morbidity benefits. Fourth, preclinical findings, while mechanistically informative, may not fully translate to humans due to species-specific microbial differences (25). Finally, the quality of included studies varied, with some RCTs lacking adequate blinding and observational studies prone to confounding, underscoring the need for rigorous trial design in future research.

Future Directions

To advance this field, large-scale, long-term RCTs are needed to assess the impact of microbiota modulation on clinical CVD outcomes, particularly in diverse populations with varying baseline risks. Personalized approaches, leveraging microbiome profiling to tailor interventions, could enhance efficacy and should be explored using advanced sequencing and metabolomic techniques (26). Standardization of intervention protocols—such as specific probiotic strains or fiber doses—would improve reproducibility and comparability across studies. Additionally, integrating microbiota modulation with existing therapies (e.g., statins, antihypertensives) could amplify benefits and warrants investigation. Finally, the role of lesser-studied modulators, such as postbiotics or antibiotics, merits further exploration to broaden therapeutic options.

Gut microbiota modulation offers a promising avenue for reducing cardiovascular risk, with dietary strategies showing the strongest evidence base and mechanistic plausibility. While probiotics, prebiotics, and FMT demonstrate potential, their clinical utility requires further validation. Addressing current limitations through rigorous, outcome-focused research will be critical to realizing the full therapeutic promise of this approach in combating the global CVD burden.

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