Microbiota in Gut‐Heart Axis: Metabolites and Mechanisms in Cardiovascular Disease

A healthy host–microorganism balance must be respected to optimally perform metabolic and immune functions and prevent disease development; it is different for everyone. Optimal gut microbiota is typically dominated by Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Fusobacteria, and Verrucomicrobia (Rinninella et al. 2019). Also, the most abundant classes are Clostridia, Bacteroidia, Bifidobacteriales, Enterobacterales, and Lactobacillales. The most abundant families include Bacteroidaceae, Lachnospiraceae, Ruminococcaceae, Odoribacteraceae, Rikenellaceae, Bifidobacteriaceae, Enterobacteriaceae, and Tannerellaceae, etc. (Dixit et al. 2021).

Everyone possesses a unique gut microbiota influenced by various factors, particularly during early life (4–36 months). This period is critical for establishing core native microbiota, shaped by gut maturation, the development of enterotypes, birth gestational age, mode of delivery, feeding practices (e.g., breastfeeding or formula feeding), weaning, lifestyle, and dietary and cultural habits (Arrieta et al. 2015; Gensollen et al. 2016). By the age of 2–3 years, the gut microbiota composition typically achieves relative stability (Rodriguez et al. 2015). For example, age‐related shifts in gut microbiota have been well‐documented, with microbial diversity decreasing in the elderly (Odamaki et al. 2016; Jandhyala et al. 2015). Similarly, the mode of delivery at birth, such as vaginal delivery versus cesarean section, significantly impacts initial microbial colonization (Nagpal et al. 2017; Wen and Duffy 2017). The composition of the gut microbiota is significantly influenced by genetic and environmental factors, which have direct implications for CVD (Abdulrahim et al. 2025; Stock 2013). Interpersonal microbiome variability has a total of 22%–36% of its origins from environmental factors, and only 1.9%–19% is linked to genetics (Rothschild et al. 2018). Studies have shown a strong link between genetic loci and changes in gut microbiota (Kurilshikov et al. 2021). A genome‐wide analysis revealed that the long‐chain triglyceride locus encoding the enzyme lactase influenced the abundance of Bifidobacterium and this study suggests that dairy intake can modulate gut microbiota genes (Qin et al. 2024). Another study has shown that genetic variants that are linked to changes in gut microbiota are also connected to a higher chance of developing coronary artery disease (Khera et al. 2018). The gut microbiome is directly influenced by environmental factors such as diet, lifestyle, and antibiotics/drugs. The nature and abundance of microbial metabolites can have either positive or negative effects on cardiovascular health. Studies show that the microbiota composition of vegetarian diets is beneficial because they increase the Prevotella enterotype, while diets with high animal protein foster the Bacteroides enterotype and other species related to proatherogenic metabolites and CVD (David et al. 2014; Kahleova et al. 2020). Certain gut microbes can reduce the effectiveness of cardiovascular drugs like digoxin; it may not be efficacious when Eggerthella lenta strains are abundant, since they inactivate this drug, while some medications like metformin can, in turn, alter the gut microbiota by increasing harmful bacterial species like Escherichia‐Shigella (Zhao and Wang 2020). It has been reported that antibiotic‐induced gut dysbiosis can activate different pathways and potentially increase the risk of CVDs (Kaur et al. 2025). Antibiotic exposure is another critical factor, often disrupting microbial balance and reducing protective species (Goodrich et al. 2014; Ley et al. 2005; Turnbaugh et al. 2009). Antibiotics such as Azithromycin, Amoxicillin, Clindamycin, Vancomycin, Cephalexin, and Ciprofloxacin are commonly used to treat bacterial infections but also affect the beneficial bacteria and disrupt gut homeostasis by reducing diverse beneficial bacterial strains such as Bifidobacterium and Lactobacillus (Duan et al. 2022; Yang et al. 2021). Tetracycline is a bacteriostatic antibiotic which suppresses bacterial growth, but it does not kill them, resulting in excess proliferation of gram‐negative bacteria E. coli and overexpression of LPS‐related genes and reducing the diversity of Bifidobacterium (Breijyeh et al. 2020; Elvers et al. 2020). The use of broad‐spectrum antibiotics Penicillin and Amoxicillin can reduce the Bacteroides, Bifidobacterium, specifically Bifidobacterium adolescentis and Bifidobacterium bifidum , and Lachnospiraceae and Ruminococcaceae (Andrei et al. 2025). Clarithromycin reduces the population of Enterobacteriaceae, Bifidobacterium, and Lactobacillus, while macrolides increase the population of Proteobacteriae (Elvers et al. 2020; Korpela et al. 2016). Studies reported that the use of broad‐spectrum antibiotics can disrupt the balance of gut microbiota and make it more danger to the development of resistant species or pathobionts, such as E. coli , Enterococcus faecalis , and Clostridium difficile (Ianiro et al. 2016). The antibiotic usage reducing the SCFAs producing bacteria such as Faecalibacterium prausnitzii , and Roseburia destroys the mucus layer and disrupts tight junctions of the intestinal barrier, making the gut prone to infections (Zhang, Cheng, et al. 2021). Recent reports show that antibiotics‐induced gut dysbiosis can activate various pathways, potentially increasing the risk of CVDs through decreases in SCFAs, bile acid metabolism and increases in TMAO production, intestinal permeability allowing LPS and TMAO into systemic circulation (Kaur et al. 2025). Perturbations in the gut microbiota have been linked to various human diseases, including CVDs (Jie et al. 2017; Cui et al. 2017; Troseid 2017) and hypertension (Li et al. 2017), and other diseases such as IBD, obesity, diabetes, allergies, and autoimmune disorders (Hasan and Yang 2019). These associations highlight the critical role of gut microbiota in health and disease (Figure 1).

Dysbiosis alters microbial diversity, diminishes beneficial taxa, and promotes pathogenic microorganisms, which can lead to systemic effects on metabolic, immune, and cardiovascular health (Table 1). Microbial signatures in dysbiosis include reduced abundance of SCFA‐producing bacteria (e.g., Faecalibacterium prausnitzii ) and beneficial genera like Akkermansia and Roseburia (Louis and Flint 2009; Geerlings et al. 2018), increased levels of opportunistic pathogens (Enterobacteriaceae, Escherichia coli ) and TMAO‐producing bacteria (Lachnoclostridium, Anaerotruncus) which are linked to cardiovascular risk (Tang and Hazen 2017; Romano et al. 2015). Understanding the factors that shape microbiota and the mechanisms linking dysbiosis to cardiovascular pathology offers new opportunities for targeted interventions to promote heart health.

One of the earliest consequences of systemic inflammation mediated by gut dysbiosis is endothelial dysfunction. Pro‐inflammatory cytokines and oxidative stress disrupt eNOS activity, reducing NO bioavailability. NO is essential for vascular homeostasis, mediating vasodilation, inhibiting leukocyte adhesion, and reducing platelet aggregation. Reduced NO levels lead to increased vascular stiffness and impaired blood flow (Maiuolo et al. 2022). Furthermore, inflammatory mediators upregulate adhesion molecules such as intercellular adhesion molecule‐1 (ICAM‐1) and vascular cell adhesion molecule‐1 (VCAM‐1). These molecules promote leukocyte adhesion and transmigration into the endothelium, exacerbating vascular inflammation and promoting atherosclerotic plaque development (Alexandrescu et al. 2024). Importantly, TMAO has been implicated in promoting endothelial inflammation and dysfunction through several mechanisms (Figure 3). TMAO inhibits the expression of sirtuin 3 (SIRT3) and the activity of superoxide dismutase 2 (SOD2), leading to the accumulation of mitochondrial ROS (mtROS). This oxidative stress activates the nucleotide‐binding oligomerization domain‐like receptor family pyrin domain‐containing 3 (NLRP3) inflammasome, resulting in the production of pro‐inflammatory cytokines IL‐1β and interleukin‐18 (IL‐18), which contribute to endothelial cell inflammation (Sun et al. 2016; Chen, Zhu, et al. 2017). Elevated circulating TMAO levels have been associated with decreased expression of sirtuin 1 (SIRT1), leading to increased oxidative stress. The resultant excessive ROS accumulation and reduced SIRT1 activity further impair NO production, adding to endothelial dysfunction (Ke et al. 2018). TMAO upregulates VCAM‐1 expression by activating the protein kinase C (PKC)/NF‐κB signaling pathway. This process directly results in endothelial dysfunction, characterized by reduced self‐repair capacity and increased monocyte adhesion to the endothelium (Ma et al. 2017).

Cardiac fibroblasts, which play a central role in maintaining the structural integrity of the heart, are also significantly affected by gut microbiota and their metabolites. Metabolites like TMAO and LPS promote the activation of cardiac fibroblasts into myofibroblasts. This transition is associated with increased extracellular matrix (ECM) deposition, leading to fibrosis and impaired myocardial compliance (Costa et al. 2022). Chronic systemic inflammation driven by gut dysbiosis enhances the secretion of pro‐inflammatory cytokines, such as IL‐6 and TGF‐β, which stimulate fibroblast activation and collagen synthesis. This contributes to pathological remodeling and heart stiffness (Melendez et al. 2010; Lijnen et al. 2000; Annes et al. 2003). Numerous animal studies have suggested that elevated TMAO levels are strongly linked to cardiac fibrosis and contribute to HF (Chen, Zheng, et al. 2017; Zhang et al. 2017; Li, Wu, et al. 2019). The profibrotic mechanisms of TMAO in the myocardium closely resemble those observed in the kidney, primarily involving TGF‐β and the NLRP3 inflammasome (Li, Geng, et al. 2019). Treatment of primary mouse cardiac fibroblasts with TMAO resulted in a dose‐dependent increase in proliferation, migration, collagen secretion, and the expression of profibrotic factors, including TGF‐β and phosphorylated SMAD3 (Li, Geng, et al. 2019). Additionally, TMAO exposure enhanced NLRP3 inflammasome activation in cardiac fibroblasts, whereas siRNA‐mediated knockdown of NLRP3 attenuated TMAO‐induced proliferation, as well as TGF‐β and collagen expression (Li, Geng, et al. 2019). A recent study demonstrates that TMAO or a high choline diet aggravates cardiac function and the transformation of fibroblasts into myofibroblasts by activating the TGF‐βRI/Smad2 pathway. It enhanced TGF‐β receptor I expression, leading to increased Smad2 phosphorylation and upregulation of α‐SMA and collagen I expression (Yang, Zhang, et al. 2019) (Figure 3). Furthermore, TMAO has been shown to drive the transformation of atrial fibroblasts into myofibroblasts via activation of the Wnt2a/β‐catenin signaling pathway (Yang, Zhang, et al. 2019; Yang, Qu, et al. 2019).

Recent studies suggest that gut‐derived metabolites, TMAO, SCFAs, and secondary BAs significantly impact cardiomyocyte physiology and pathology through various mechanisms (Zhang, Wang, et al. 2021). Elevated TMAO levels are associated with adverse cardiovascular outcomes, including HF, arrhythmias, and myocardial fibrosis (Zhen et al. 2023). TMAO in cardiomyocytes triggers TGF‐β1/Smad3/p65 NF‐κB signaling pathways and lowers energy metabolism and mitochondrial function by disrupting pyruvate and fatty oxidation, as well as the TCA cycle. TMAO also increased the expression levels of atrial natriuretic factor (ANP) and β‐myosin heavy chain (β‐MHC), which caused myocardial hypertrophy and fibrosis through activation of the TGF‐β1/Smad3 pathway (Li, Wu, et al. 2019) (Figure 3). It also adversely affects myocardial contractile function and intercellular calcium processing (Li, Wu, et al. 2019; Makrecka‐Kuka et al. 2017; Savi et al. 2018). Recent studies highlight TMAO's complex effects on mitochondrial function and cardiomyocyte health (Wang et al. 2011; Tang et al. 2013). TMAO impairs mitochondrial function in cardiomyocytes by disrupting mitochondrial respiration and OXPHOS, leading to reduced ATP production and energy metabolism (Li et al. 2023). It also increases mitochondrial oxidative stress by inhibiting key antioxidant enzymes and promotes inflammation and induces cardiomyocyte apoptosis (Li et al. 2023). However, these effects are dose and time dependent, and more research is needed to explore specific mechanisms of TMAO.

On the other hand, as mentioned above, SCFAs, particularly butyrate and propionate, exhibit cardioprotective effects by enhancing mitochondrial efficiency, reducing ROS production, and attenuating inflammatory responses in cardiomyocytes. These actions preserve myocardial function and limit ischemic injury (Wang and Zhao 2018; Yukino‐Iwashita et al. 2022; Li et al. 2012; Kessler‐Icekson et al. 2012). These findings suggest that gut dysbiosis contributes to CVD through enhanced systemic inflammation inducing endothelial dysfunction, fibroblast activation, and cardiomyocyte impairment, eventually leading to CVD.

The gut microbiota plays a crucial role in shaping the immune system, influencing both local and systemic immune responses. Dysbiosis disrupts this balance, leading to heightened immune activation and chronic low‐grade inflammation—a recognized driver of CVD. In a healthy state, the gut microbiota promotes immune tolerance through Treg activation and the production of anti‐inflammatory cytokine IL‐10, thus maintaining immune homeostasis and preventing excessive inflammation. Dysbiosis reduces the abundance of beneficial microbes like Faecalibacterium prausnitzii and Akkermansia muciniphila , which are critical for maintaining immune homeostasis (Zheng et al. 2020; Yoo et al. 2022; Mousa et al. 2022; Effendi et al. 2022). This imbalance skews the immune response toward a pro‐inflammatory state, characterized by elevated levels of pro‐inflammatory cytokines such as IL‐6 and TNF‐α (Zheng et al. 2020). Gut dysbiosis increases the translocation of microbial components such as LPS, peptidoglycans, and bacterial DNA into systemic circulation due to impaired intestinal barrier function. These components activate pattern recognition receptors (PRRs), including TLRs and NLRs, on immune cells. As mentioned before, LPS binds to TLR4, triggering a cascade of pro‐inflammatory signaling pathways that amplify systemic inflammation and contribute to endothelial dysfunction (Yoo et al. 2020; Maiuolo et al. 2022; Zheng et al. 2020). In addition to innate immune activation, dysbiosis modulates adaptive immunity by altering antigen presentation and T‐cell polarization. Increased microbial translocation promotes the activation of effector T‐cells, particularly Th17 cells, which secrete interleukin‐17 (IL‐17), a cytokine implicated in vascular inflammation and atherosclerosis (Zheng et al. 2020; Nesci et al. 2023).

The gut microbiota plays a crucial role in modulating cardiovascular health through its interactions with neurohumoral and hormonal pathways (Singh et al. 2024). Previous investigations have revealed SCFA‐mediated sympathetic nerve activity by activating GPR41, which in turn is linked to the regulation of BP and hypertension (Onyszkiewicz et al. 2019; Xu et al. 2022; Kimura et al. 2011). Additionally, the vagus nerve serves as a crucial communication pathway between the gut and the brain, playing a significant role in regulating cardiovascular function and anti‐inflammatory signaling. Gut dysbiosis reduces vagal tone, impairing its ability to regulate inflammatory responses. Decreased vagal activity results in unchecked inflammation, promoting vascular damage and atherosclerosis (Bonaz et al. 2017; Gidron et al. 2007). Gut dysbiosis has been linked to the dysregulation of the renin‐angiotensin‐aldosterone system (RAAS), a critical regulator of BP and fluid homeostasis. Studies suggest that altered gut microbiota composition influences angiotensin II levels, promoting vasoconstriction, oxidative stress, and inflammation—hallmarks of hypertension and CVD (Tang et al. 2017; Karbach et al. 2016; Mell et al. 2015). Additionally, gut microbiota significantly affects metabolic hormones such as insulin, glucagon‐like peptide‐1 (GLP‐1), and ghrelin. Alterations in GLP‐1 production impair glucose metabolism and lipid homeostasis, increasing the risk of metabolic syndrome (Festi et al. 2014). Furthermore, disruption in the secretion of ghrelin indirectly influences cardiovascular risk factors such as obesity and hypertension (Aron‐Wisnewsky et al. 2021). Gut dysbiosis affects estrogen metabolism through the gut‐liver axis. Microbial beta‐glucuronidase enzymes modulate circulating estrogen levels, and dysbiosis can lead to hormonal imbalances that influence vascular function and inflammation, particularly in postmenopausal women at increased risk for CVD (Baker et al. 2017). Thus, the interplay between gut dysbiosis and neurohumoral and hormonal pathways underscores its pivotal role in CVD pathogenesis.

Hypertension, defined as persistent high BP, is a significant global health challenge associated with an increased risk of CVDs (Mills et al. 2020). Emerging evidence suggests that the gut microbiota plays a crucial role in the regulation of hypertension pathogenesis through its metabolites, particularly SCFAs and TMAO and secondary BAs (Poll et al. 2020; Ishimwe et al. 2022). As mentioned previously, SCFAs, primarily butyrate, propionate, and acetate, are produced by the fermentation of dietary fiber by gut microbiota (Rios‐Covian et al. 2016). Butyrate, produced by bacteria such as Clostridium, Eubacterium, and Roseburia, has multiple mechanisms contributing to BP regulation. It activates GPR41 and GPR43 on VECs, thereby reducing vascular resistance and lowering BP (Gerard 2013; Heaton 1969); mitigates systemic inflammation and oxidative stress, both of which are central to the development of hypertension (Mayerhofer et al. 2017); maintains the gut barrier by preventing the translocation of pro‐inflammatory substances into the bloodstream, thereby reducing factors that elevate BP (Li, Shu, et al. 2020); and modulates serotonin release from enterochromaffin cells (ECCs), enhancing gut‐brain axis signaling and influencing CNS mechanisms involved in BP regulation (Zhang and Gerard 2022). Acetate produced by bacteria such as Faecalibacterium and Roseburia, plays a pivotal role by serveing as a precursor for butyrate production and also independently induces vasodilation, reducing vascular resistance (Marques et al. 2017; Cookson 2021); enhances serotonin release from EECs by modulating the gut‐brain axis to regulate BP (Cookson 2021). Acetate supplementation in the drinking water of deoxycorticosterone acetate (DOCA)‐salt hypertensive mice resulted in reduced systolic and diastolic BP, as well as attenuation of cardiac fibrosis and hypertrophy (Marques et al. 2017). Acetate further reduces mean arterial pressure (MAP) and heart rate (HR) by influencing the autonomic nervous system, including reducing sympathetic tone and cardiac contractility (Poll et al. 2020). Propionate, generated by bacteria like Veillonellaceae and Prevotella, provides additional cardiovascular benefits such as reverses T‐cell imbalances caused by hypertension, aiding in cardiac remodeling (Bartolomaeus et al. 2019), activates GPR41 and GPR43 on cardiac fibroblasts, inhibiting myofibroblast formation and reducing collagen production, thereby protecting against fibrosis and vascular dysfunction. Furthermore, acetate and propionate jointly reduce cardiac hypertrophy, vascular dysfunction, and immune cell infiltration, improving heart function under stress (Lin et al. 2022).

In contrast to SCFAs, TMAO has been implicated in hypertension and other cardiovascular disorders. As described in the above section, elevated levels of TMAO are strongly linked to adverse cardiovascular outcomes, including endothelial dysfunction, atherosclerosis, and thrombosis. TMAO plays a pivotal role in endothelial dysfunction by driving inflammation, increasing oxidative stress, and impairing vascular reactivity—key mechanisms that contribute to the development and progression of hypertension. Mechanistically, TMAO promotes oxidative stress and impairs NO signaling, leading to vasoconstriction and hypertension (Shanmugham et al. 2023).

HF is a complex clinical syndrome characterized by the heart's inability to pump sufficient blood to meet the body's needs. Emerging evidence highlights that HF is associated with alterations in gut microbiota composition, favoring pro‐inflammatory and pathogenic species. The “gut hypothesis of heart failure” proposes that HF‐induced factors, including reduced intestinal perfusion and altered gut motility, disrupt gut microbiota composition, and increase intestinal permeability. These conditions further compromise tight junctions, weakening the gut barrier's integrity (Matacchione et al. 2024; Harikrishnan 2019; Sandek et al. 2008). Concurrently, venous congestion causes intestinal edema, exacerbating epithelial barrier dysfunction (Sandek et al. 2008). Oxidative stress, another hallmark of HF, damages epithelial cells and impairs the synthesis of protective mucins, thereby aggravating gut barrier breakdown (Yuzefpolskaya et al. 2020). This leads to a compromised intestinal barrier, a selective interface between the host and gut microbiota, resulting in increased gut permeability. As mentioned before, the alteration in gut permeability leads to an increased passage of pathogens and toxins, such as LPS, from the gut into the systemic circulation. This state of “leaky gut” is associated with chronic systemic inflammation, characterized by elevated pro‐inflammatory cytokines, including TNF‐α, IL‐6, and IL‐1β, which contribute to myocardial remodeling and cardiac dysfunction and can exacerbate HF symptoms and severity (Tang et al. 2017; Lupu et al. 2023; Pasini et al. 2016).

Atherosclerosis is a chronic, progressive disease characterized by the accumulation of lipids, inflammatory cells, and fibrous elements in the arterial wall, leading to the formation of plaques. These plaques can block blood flow and lead to heart attacks, strokes, and other cardiovascular problems (Lusis 2000). In recent years, multiple studies have confirmed the presence of bacterial DNA in atherosclerotic plaques, suggesting a potential role in the development of CVD (Ott et al. 2006). Additionally, differences in gut microbiota composition have been observed between individuals with and without atherosclerosis. Garshick et al. transplanted aortas from atherosclerotic Apoe^−/− mice into normolipidemic wild‐type (WT) recipients, followed by antibiotic treatment. Although plaque size remained similar to that in Apoe^−/− donors, there was a 32% reduction in CD68⁺ macrophages, suggesting that antibiotics delay atherosclerosis inflammation resolution and that gut microbiota play a role in atherosclerosis inflammation (Garshick et al. 2021). Studies found that patients with CHD or elevated intima‐media thickness (IMT), a marker of subclinical atherosclerosis, exhibited a higher Firmicutes/Bacteroidetes ratio, which is often linked to obesity and gut dysbiosis—highlighting the protective role of butyrate in CVD (Cui et al. 2017; Szabo et al. 2021). Additionally, other studies reported an enrichment of Escherichia in individuals with subclinical carotid atherosclerosis (SCA) and coronary artery disease (CAD), suggesting its potential as a predictive marker for atherosclerosis progression (Zhu et al. 2018; Baragetti et al. 2021). Ji et al. further identified an increased abundance of Acidaminococcus in patients with carotid atherosclerosis (CAS), a genus linked to inflammatory diseases and proinflammatory diets, suggesting its possible role as a proinflammatory microbiota in atherosclerosis development (Ji et al. 2021). Mitra et al. reported significant differences in gut microbiota composition between patients with stable versus unstable plaques (Mitra et al. 2015), whereas Hallenius et al. found no major differences in bacterial DNA content or microbial composition between the two. Some researchers suggest that bacterial DNA may activate macrophages and trigger the innate immune system via TLR2 and TLR4, which influence plaque stability (Mitra et al. 2015; Lindskog Jonsson et al. 2017).

Further research by Chen et al. demonstrated the feasibility of gut microbiome remodeling to prevent the onset and progression of atherosclerosis in LDLr^−/− mice, reinforcing the potential role of gut microbiota in atherosclerosis and its therapeutic implications. Additionally, one study found that introducing proinflammatory Casp1^−/− microbiota into LDLr^−/− mice promoted plaque growth, neutrophil accumulation, and a reduction in SCFAs‐producing taxa (Akkermansia, Christensenellaceae, Clostridium, and Odoribacter) (Chen et al. 2020).

Probiotics are live microorganisms that confer health benefits to the host when administered in adequate amounts. Specific strains of Lactobacillus and Bifidobacterium have demonstrated the ability to reduce gut permeability, suppress inflammation, and improve lipid profiles—all critical factors in cardiovascular health. For instance, Lactobacillus plantarum supplementation reduced BP and improved endothelial function in preclinical models (Malik et al. 2018). Probiotics also lower TMAO levels by modulating microbial populations responsible for TMA production, such as Lactobacillus plantarum ZDY04 (Qiu et al. 2018). Prebiotics, such as inulin and fructooligosaccharides, serve as substrates for beneficial gut bacteria. These compounds enhance the production of SCFAs like butyrate, which have anti‐inflammatory and vasodilatory effects. In vitro and in vivo studies suggest that the anti‐inflammatory and immunomodulatory properties of herbs and functional foods, such as Ocimum sanctum, Zingiber officinale , and Piper nigrum , may be linked to their prebiotic activity (Babu et al. 2018; Kondapalli et al. 2022). This is attributed to the presence of phytochemicals that help regulate gut microbiota, thereby reducing systemic inflammation and related disorders. Clinical studies show that prebiotic supplementation improves arterial stiffness and lowers systemic inflammation, thereby reducing cardiovascular risk (Pavlidou et al. 2022). While whole foods rich in natural fibers support beneficial gut bacteria and offer numerous health benefits, however, a recent study reveals that consumption of highly refined fermentable fibers may adversely affect liver health, leading to the development of icteric hepatocellular carcinoma (Singh et al. 2018). These discrepancies point to the fact that the activity of gut metabolites and signaling mediators is highly context‐dependent, influenced by variables such as dietary inputs, gut microbiota composition, host health status, and metabolic individuality. These factors collectively determine whether a metabolite exerts beneficial, neutral, or detrimental effects.

Synbiotics combine probiotics and prebiotics to synergistically enhance gut health. By delivering beneficial microbes and their specific growth substrates, synbiotics optimize the gut microbiota's functionality. Synbiotics leverage the complementary effects of probiotics and prebiotics, enhancing colonization resistance, SCFA production, and immunomodulation. Synbiotics have demonstrated that regular consumption of synbiotic yogurts can lower the risk of CVDs in hypercholesterolemic patients (Pavlidou et al. 2022). Additionally, a study found that 12 weeks of synbiotic supplementation resulted in a reduction of ICAM‐1 levels, a key risk factor for CVDs, in hemodialysis patients (Haghighat et al. 2019). All these interventions offer promising avenues for modulating gut microbiota, reducing inflammation, improving lipid profiles, and ultimately mitigating cardiovascular risk.

The Mediterranean diet, rich in fiber, polyphenols, and unsaturated fats, promotes a healthy gut microbiome and reduces cardiovascular risk factors. Increased fiber intake supports the growth of SCFA‐producing bacteria, enhancing gut barrier integrity and reducing systemic inflammation. Dietary modifications, such as reducing red meat and egg consumption, can lower TMAO levels. This, in turn, mitigates endothelial dysfunction and atherosclerotic progression linked to TMAO (Abrignani et al. 2024).

New pharmacological agents aim to selectively modulate gut microbiota composition. Drugs targeting TMAO production, such as 3,3‐dimethyl‐1‐butanol (DMB), inhibit microbial enzymes involved in TMA formation. DMB has shown efficacy in reducing TMAO levels and attenuating atherosclerosis in animal models (Wang et al. 2015). Direct supplementation of SCFAs, particularly butyrate, has been explored for its cardioprotective effects (Challa and Lewandowski 2022). Butyrate improves endothelial function, reduces oxidative stress, and modulates BP regulation via G protein‐coupled receptor activation (Amiri et al. 2021). Antibiotics targeting specific TMA‐producing bacteria have shown promise in modulating TMAO levels and potentially influencing cardiovascular outcomes. In healthy participants, administration of broad‐spectrum antibiotics significantly reduced plasma TMAO levels after a phosphatidylcholine challenge. However, it is crucial to note that chronic antibiotic use may have adverse consequences, such as the emergence of antibiotic‐resistant bacterial strains and potential metabolic disturbances (Yang, Li, et al. 2019). Bile acid modulators represent another class of drugs that can influence cardiovascular outcomes by altering gut microbiota composition and function. These agents can affect bile acid pool size and composition, which in turn impacts cholesterol metabolism and TMAO production. By modulating bile acid signaling through FXR, these drugs may offer a novel approach to managing CVD risk (Nesci et al. 2023).

Several established pharmacotherapies for CVDs are now recognized to alter the gut microbiome, with growing evidence that these interactions may influence both drug efficacy and cardiovascular outcomes. The captopril is a first‐generation angiotensin‐converting enzyme inhibitor (ACE‐Is); which not only lowers BP but also alters the gut microbiota composition. In a preclinical study, captopril‐induction, reduces the BP and alters the gut microbiome in spontaneously hypertensive (SHR) rats (Yang, Aquino, et al. 2019). Maternal captopril treatment led to persistent antihypertensive effects in offspring via reconstitution of the gut microbiota, including increased Clostridia and Clostridiales (Li, Yang, et al. 2020). Benazepril and Enalapril are the second‐generation ACE‐Is also impact the gut microbiome. Benazepril promotes restoration of gut microbiota structure, while enalapril has been shown to reduce blood levels of TMAO. Enalapril achieves this by modifying gut microbiota composition and increasing urinary excretion of methylamines (Zhao et al. 2023). Statins (e.g., simvastatin, rosuvastatin, atorvastatin) are widely used lipid‐lowering agents. Metagenomic studies have shown that statin use is associated with significant shifts in gut microbiota composition (Wilmanski et al. 2022). Statins may also decrease the amount of secondary BAs and alter signaling through the FXR, which is influenced by gut microbial metabolism (Tuteja and Ferguson 2019). Antihypertensive medications such as, amlodipine, a calcium channel blocker is metabolized presystemically by gut microbial dehydrogenation, which may reduce the amount of active drug reaching target tissues. Its use has also been associated with changes in gut microbiota, though the specific bacterial taxa involved are not fully characterized. Other cardiovascular drugs including, β‐blockers and α‐blockers have found associations between the use of these antihypertensive agents and alterations in gut bacterial taxa, though the precise mechanisms and clinical implications remain under investigation. An antidiabetic agent, metformin is frequently used in patients with CVD and has been shown to significantly alter the gut microbiota. It increases the abundance of beneficial bacteria such as Akkermansia muciniphila , which is linked to improved metabolic and cardiovascular outcomes (Witkowski et al. 2020; Masenga et al. 2022).

Fecal microbiota transplantation involves transferring processed stool from a healthy donor into the gastrointestinal tract of a patient, aiming to restore a balanced and diverse gut microbiome (Ponce Alencastro et al. 2025). This intervention is based on the principle that many diseases, especially those involving gut dysbiosis, can be improved by reintroducing beneficial microbial communities (Cammarota et al. 2014). The therapeutic effect of FMT is thought to arise from: (i) Replacing missing or depleting beneficial bacteria; (ii) Competing with pathogenic microbes (bacterial interference); (iii) Restoring production of key metabolites (e.g., SCFAs, secondary BAs); (iv) Modulating immune system and metabolic pathways. Clinically, FMT has shown some beneficial effects for the treatment of Clostridium difficile (CD)‐associated diarrhea (Cammarota et al. 2014). However, the studies that show the effects of FMT on metabolic parameters remain controversial. A meta‐analysis report on cardiometabolic risk factors demonstrated that no significant changes were seen in lipid profiles, blood glucose, and insulin resistance (Pakmehr et al. 2024). However, various other studies were reported with changes in the lipid profile including reduction in LDL (p < 0.04) and total cholesterol (p < 0.05). Mean triglycerides (TG) were reduced significantly from 3.9 mmol/L to 2.62 mmol/L (Ng et al. 2022). Preclinical studies indicate that FMT can restore microbial diversity and reduce systemic inflammation, leading to improvements in cardiovascular health. For example, FMT from healthy individuals to hypertensive patients showed a transient reduction in BP (Fan et al. 2022). In a randomized clinical trial (NCT04406129↗), hypertensive patients (n = 124) received FMT capsules shown to decrease in systolic BP after 1 week of FMT, but this difference did not maintain even after repeated interventions; however, it was notified that it was safe (Fan et al. 2025). Therefore, further detailed studies are required to establish the facts and also to advance the FMT‐based clinical interventions to treat CVDs.

In addition to FMT, postbiotics, nonviable microbial products such as SCFAs, enzymes, and peptides are being investigated for their cardiovascular benefits. They offer the advantage of stability and targeted delivery without the risks associated with live organisms (Rahimi et al. 2024). Regular physical activity is a natural and effective way to prevent or mitigate gut dysbiosis, which plays a key role in CVDs. Targeting the gut microbiome through exercise, alongside dietary interventions, may offer novel therapeutic approaches for CVD prevention and management (Yan et al. 2021).

Targeting the gut‐heart axis through probiotics, prebiotics, dietary interventions, pharmacological agents, and emerging strategies like FMT offers promising avenues for CVD management. These approaches highlight the potential of gut microbiota modulation in reducing systemic inflammation, improving lipid profiles, and enhancing overall cardiovascular health.

The authors have nothing to report.