The Gut–Heart Axis: A Comprehensive Review of Microbiota’s Role in Cardiovascular Health and Disease and Emerging Therapeutic Strategies

The human GI microbiome consists of distinct microbial communities that vary along the GI tract.•Esophagus: The distal esophageal microbiome exhibits low diversity, with Streptococcus species being the dominant group. Other genera, including Prevotella, Actinomyces, Lactobacillus, and Staphylococcus, have also been identified [21].•Stomach: Though historically considered inhospitable to bacteria, the stomach harbors Helicobacter pylori, significantly affecting microbial composition. Other acid‐resistant bacteria include Streptococcus, Neisseria, and Lactobacillus. Studies have identified dominant genera such as Pasteurellaceae, Veillonella, Rothia, Streptococcus, and Prevotella [22–24].•Small intestine: The duodenum is colonized primarily by Firmicutes and Actinobacteria, while the jejunum hosts facultative anaerobes like Lactobacillus, Enterococcus, and Streptococcus. The ileum harbors a microbiota resembling that of the colon, consisting mainly of anaerobes and Gram‐negative organisms [21].•Large intestine: Dominated by Firmicutes and Bacteroidetes, the colon also harbors opportunistic pathogens like Bacteroides thetaiotaomicron and Bacteroides fragilis [21].

The gut microbiota plays a crucial role in host health by contributing to various metabolic and immune processes.•Dietary fiber metabolism: The gut microbiota ferments dietary fiber into SCFAs (e.g., acetate, propionate, butyrate), which regulate intestinal homeostasis and inflammation [1].•Immunity: The gut microbiota plays a central role in shaping the immune system, promoting gut‐associated lymphoid tissue (GALT) development, and modulating systemic inflammation [19, 25].•Lipid metabolism: Gut microbes influence energy balance, glucose metabolism, and lipid metabolism, impacting conditions like obesity and metabolic syndrome [26].•Bile acid metabolism: Gut bacteria convert primary bile acids into secondary metabolites that regulate cholesterol homeostasis and lipid absorption [19].•Tryptophan metabolism: The microbiota metabolizes tryptophan into bioactive compounds such as indoles, influencing immune function and inflammation [19].•SCFAs: SCFAs modulate immune responses and maintain intestinal integrity by influencing regulatory T‐cell function and mucosal defense [19, 25–28].•Choline metabolism: Gut bacteria convert choline into trimethylamine (TMA), which is oxidized into TMAO, a compound linked to CVD [1, 29].•Gut–brain axis: The microbiota interacts with the enteric and central nervous systems, influencing neurodevelopment and cognitive function [30, 31].

The relationship between the host and gut microbiota is primarily commensal but can shift to pathogenic under dysbiotic conditions. The host employs feedback mechanisms to maintain microbial equilibrium, including immune modulation, spatial segregation of microbes, and alternative nutrient provision. Understanding the composition and function of the gut microbiota is essential for developing targeted interventions to improve CV and overall health [1].

Fecal microbiota transplantation (FMT) serves as a critical experimental model to establish causality rather than a naturally occurring physiological mechanism. Germ‐free animal models have been instrumental in elucidating the functional role of gut microbiota in disease susceptibility. Studies have demonstrated significant increases in blood pressure following FMT from hypertensive individuals into germ‐free mice, thereby establishing a direct link between gut microbiota composition and hypertension [34, 35]. Additionally, specific bacterial species have been implicated in modulating CV health. For instance, the colonization of germ‐free ApoE‐deficient mice with the butyrate‐producing bacterium Roseburia intestinalis has been shown to reduce inflammatory markers and inhibit the progression of atherosclerotic lesions [36]. Furthermore, FMT between mouse strains with differing susceptibilities to atherosclerosis has revealed that gut microbiota composition plays a crucial role in disease development [37]. These findings emphasize the importance of both individual bacterial species and overall microbial community structure in influencing CVD risk.

Dysbiosis, an imbalance in microbial communities, lacks a universally standardized definition and can oversimplify complex microbial dynamics. For the purpose of this review, we define dysbiosis as a maladaptive imbalance in the microbial community structure, characterized by a loss of diversity, a reduction in beneficial commensals, and an expansion of pathobionts—that disrupts host–microbe homeostasis and contributes to disease pathology [38]. A healthy gut microbiota is characterized by a balanced ratio of Bacteroidetes to Firmicutes, which varies along the alimentary tract due to factors such as pH, oxygen levels, and nutrient availability [38]. Early studies utilizing 16S rRNA gene sequencing identified bacterial taxa associated with coronary artery disease (CAD) [39].

Research has shown that CAD patients exhibit elevated levels of Lactobacillales (Firmicutes) and reduced levels of Bacteroidetes (Bacteroides and Prevotella) [40]. Moreover, metagenomic analyses have found that individuals with atherosclerotic CVD harbor increased levels of Enterobacteriaceae and oral bacteria while displaying lower levels of butyrate‐producing bacteria [41]. HF patients demonstrate decreased microbial diversity, core microbiota depletion, and increased susceptibility to Clostridium difficile infections [42, 43]. Additionally, conditions of elevated right atrial pressure have been linked to increased mucosal biofilm formation, bacterial overgrowth, and colonization by pathogenic species such as Candida, Campylobacter, and Shigella [44]. Notably, reductions in butyrate‐producing bacteria, including Faecalibacterium prausnitzii and Lachnospiraceae, correlate with elevated inflammatory markers across HF patient populations [42, 45].

Growing evidence suggests that gut microbiota influence CV health by modulating immune cell activity, particularly T‐cell function [46, 47]. Microbiota transfer from inflammatory‐prone mice to atherosclerosis‐prone mice has been shown to accelerate atherosclerotic plaque formation, likely due to elevated systemic inflammatory cytokines such as interleukin (IL)‐1β, IL‐2, and interferon (IFN)‐γ [48, 49]. Conversely, supplementation with Bacteroides vulgatus and Bacteroides dorei has been found to reduce plasma tumor necrosis factor‐alpha (TNF‐α) levels and atherosclerotic lesions [49]. Similarly, administering Lactobacillus plantarum ATCC 14917 mitigated lesion formation by decreasing oxidized LDL, TNF‐α, and interleukin‐1 beta (IL‐1β) levels. The presence of Roseburia and Blautia has been associated with lower plasma cholesterol, TNF‐α, IL‐1β, and atherosclerotic burden [50, 51]. Additionally, dietary salt intake has been linked to hypertension via gut microbiota alterations. High salt consumption depletes Lactobacillus murinus, resulting in increased blood pressure, while supplementation restores balance by modulating T helper 17 (TH17) cell activity, thereby providing potential therapeutic avenues for hypertension management [52].

The intestinal barrier, composed of mucus layers, tight junctions, and immune defenses, prevents bacterial translocation. This relationship is bidirectional: barrier compromise allows LPS translocation, but LPS itself, a structural component of Gram‐negative bacterial cell walls, can directly impair tight junction proteins, further increasing permeability and creating a vicious cycle of endotoxemia and inflammation [53]. Patients with CVD exhibit elevated endotoxin levels, with hepatic vein blood containing higher concentrations than ventricular blood [54, 55]. Certain bacterial species, such as Akkermansia muciniphila, help maintain intestinal integrity. Treatment with A. muciniphila has been shown to reduce endotoxemia and aortic atherosclerosis in ApoE‐deficient mice [56]. Human studies further support the therapeutic potential of pasteurized A. muciniphila, which was found to lower circulating LPS levels in obese individuals [57]. These findings suggest that strategies aimed at strengthening intestinal barrier function and modulating gut microbiota may offer promising avenues for CVD prevention and treatment.

The gut microbiota functions as a metabolic organ, producing bioactive compounds that act as signaling molecules in the host’s systemic circulation. The balance between protective and pro‐atherogenic metabolites is a primary determinant of CV health.

SCFAs, produced primarily by the fermentation of dietary fibers by bacteria such as Faecalibacterium and Roseburia (including acetate, propionate, and butyrate) exert crucial cardioprotective effects. Mechanistically, SCFAs function as histone deacetylase (HDAC) inhibitors, which downregulate pro‐inflammatory gene expression in the vascular endothelium. Furthermore, they interact with G‐protein‐coupled receptors (GPR41 and GPR43) to regulate blood pressure via renin secretion control and vasodilation [58, 59]. Conversely, TMAOs represents a key pro‐atherogenic metabolite. Gut bacteria metabolize dietary nutrients containing TMA moieties, specifically choline, phosphatidylcholine, and L‐carnitine found in red meat and eggs into TMA [60]. TMA is absorbed and oxidized in the liver by flavin‐containing monooxygenases (FMO3) to form TMAO. TMAO promotes CV pathology through three distinct mechanisms: (1) inhibition of reverse cholesterol transport, (2) upregulation of scavenger receptors (CD36 and SR‐A1) on macrophages leading to foam cell formation, and (3) enhancement of platelet hyper‐reactivity and thrombosis risk [60–63].

Dysbiosis‐induced barrier dysfunction facilitates the translocation of LPS, an endotoxin, into the circulation. LPS binds to Toll‐like receptor 4 (TLR4) on endothelial and immune cells, triggering the NF‐κB inflammatory cascade and driving systemic inflammation [64, 65]. Additionally, gut bacteria modulate the bile acid pool; secondary bile acids act as signaling molecules on farnesoid X receptors (FXR) and TGR5, influencing lipid and glucose metabolism [65]. Collectively, these findings highlight the dual impact of gut microbiota metabolites on CV health, with SCFAs exerting protective effects while TMAO and LPS contribute to disease progression. Maintaining microbial balance is thus essential for CV health [60–65]. Figure 1 explores the integrated mechanistic pathway of the gut–heart axis, and Table 1 outlines a comprehensive summary of microbial influences on CV function.

Atherosclerosis is a chronic inflammatory condition driven by dysregulated lipid metabolism and an inappropriate immune response, leading to cholesterol‐rich macrophage accumulation within arterial walls [66]. Research utilizing 16S rRNA gene pyrosequencing has revealed that atherosclerotic plaques contain bacterial DNA with phylotypes commonly found in the gut microbiota. The quantity of bacterial DNA in plaques is correlated with inflammation, suggesting potential microbial translocation [66, 67]. Certain bacteria, such as Streptococcus and Veillonella, can directly influence plaque composition, while Pseudomonas, Klebsiella, and Chlamydia pneumoniae have also been identified within atherosclerotic lesions [68]. However, most studies have not established a definitive link between plaque microbiota composition and clinical outcomes such as plaque rupture or CV events [68–70].

Metabolically, the progression of atherosclerosis is heavily influenced by the TMAO pathway described in Section 4.5. Elevated plasma TMAO levels are strongly correlated with increased atherosclerotic burden and major adverse cardiovascular events (MACE) in humans [71]. In animal models, dietary suppression of TMA generation attenuates plaque formation, confirming a causal role [72]. Conversely, the depletion of SCFA‐producing bacteria reduces the availability of butyrate, removing its protective inhibition of vascular inflammation and accelerating plaque progression [72–74].

Hypertension is a major modifiable risk factor for CVD and is strongly associated with gut microbiota dysregulation [75, 76]. Alterations in microbial composition include an increased Firmicutes‐to‐Bacteroidetes (F/B) ratio, a reduction in SCFA‐producing bacteria, an expansion of lactic acid bacteria, and an increase in Proteobacteria and Cyanobacteria [69].

Mechanistically, the reduction of SCFAs impairs blood pressure regulation. As noted in Section 4.5, SCFAs normally interact with GPR41 to mediate vasodilation. In hypertensive animal models, reduced SCFA availability leads to increased peripheral vascular resistance and vascular remodeling [77–80]. Furthermore, high salt intake, a known risk factor for hypertension, has been shown to deplete Lactobacillus murinus; supplementing with this bacterium prevents salt‐sensitive hypertension by modulating T helper 17 (TH17) cell activity. Conversely, elevated TMAO levels contribute to hypertension by prolonging the pressor effects of angiotensin II and inducing endothelial dysfunction via oxidative stress [81–83]. Probiotic interventions aimed at restoring the SCFA‐producing population have shown promise in lowering systolic blood pressure by mitigating these vascular inflammatory responses [84].

Atrial fibrillation (AF) is the most common sustained arrhythmia and is increasingly linked to the systemic inflammation driven by gut dysbiosis. The “gut‐heart” connection in AF is mediated primarily through inflammatory signaling and structural remodeling of the atria [85]. Dysbiosis contributes to AF progression by compromising the intestinal barrier, leading to elevated circulating LPS [85–87]. LPS activates NLRP3 inflammasomes in atrial cardiomyocytes, promoting the release of pro‐inflammatory cytokines IL‐1β and IL‐18. This inflammatory milieu promotes atrial fibrosis, a substrate for re‐entrant arrhythmias [86]. Additionally, elevated TMAO levels have been implicated in enhancing atrial autonomic remodeling and increasing susceptibility to AF [88–90]. TMAO promotes M1 macrophage infiltration in atrial tissue, exacerbating inflammation and fibrosis. Conversely, bile acids modulate this risk; the activation of FXR by secondary bile acids has been shown to inhibit the inflammatory cascades that trigger AF, suggesting that maintaining a healthy bile acid metabolism is protective against arrhythmia development [91–94]. Figure 2 illustrates the relationship between gut microbiota, inflammation, and AF.

HF is primarily caused by myocardial dysfunction resulting from conditions such as CAD, hypertension, and metabolic disorders [95]. Emerging evidence highlights a bidirectional relationship between gut microbiota and HF. Dysbiosis induces systemic inflammation, oxidative stress, and metabolic dysregulation, exacerbating myocardial dysfunction [95, 96].

According to the “gut hypothesis of HF,” alterations in gut permeability and microbiota composition—caused by reduced cardiac output, intestinal edema, and altered gut motility—worsen HF outcomes [97]. Patients with HF exhibit increased intestinal colonization by pathogenic bacteria such as Campylobacter, Shigella, and Salmonella, leading to enhanced systemic inflammation [44]. Additionally, LPS binds to Toll‐like receptor 4 (TLR4) on cardiomyocytes, cardiac fibroblasts, and macrophages, promoting pro‐inflammatory cytokine release and myocardial damage via NLRP3 inflammasome activation [98, 99].

SCFA‐producing bacteria, including Eubacterium, Faecalibacterium, and Ruminococcus, are reduced in HF patients, whereas overgrowth of proinflammatory Proteobacteria is commonly observed [100, 101]. Restoring gut microbiota balance through probiotic or prebiotic interventions has demonstrated improvements in inflammatory markers and clinical outcomes [102]. TMAO contributes to myocardial hypertrophy and fibrosis by activating Smad3 signaling, leading to left ventricular dilation and increased brain natriuretic peptide levels. Additionally, inflammaging, a chronic low‐grade inflammatory state associated with aging, has been linked to gut dysbiosis in elderly HF patients [103–105].

Gut microbiota and its metabolites regulate the progression of neurological disorders, including ischemic stroke [106]. Dysbiosis alters the intestinal environment, affecting nutrient absorption, immune homeostasis, and systemic metabolism, thereby increasing the risk of ischemic stroke via mechanisms such as hypertension and diabetes [107]. Furthermore, stroke severity and prognosis are influenced by gut microbiota alterations, which modulate immune responses, inflammation, and thrombosis [108].

The microbiota–gut–brain axis facilitates bidirectional communication between the gut and central nervous system through neural, endocrine, and immune pathways [109–111]. Microbial metabolites such as SCFAs contribute to brain–gut barrier integrity, mitigate oxidative stress, and reduce neuroinflammation following an acute ischemic stroke (AIS) [112]. Additionally, poststroke bacterial translocation may contribute to stroke‐associated infections, with autonomic nervous system overactivation and excessive glucocorticoid release exacerbating gut dysbiosis and intestinal permeability [113].

Dysbiosis has been implicated in increased venous thromboembolism risk, particularly by reducing beneficial commensal bacteria and an overgrowth of pathogenic Gram‐negative bacteria, such as Enterobacteriaceae. LPS, a glycolipid component of the Gram‐negative bacterial outer membrane, induces hypercoagulability by binding Toll‐like receptors on endothelial cells and platelets, activating the coagulation cascade. TMAO enhances platelet hyper‐reactivity and promotes thrombus formation, further increasing pulmonary thromboembolism susceptibility [114].

Recent research has explored prebiotic and probiotic interventions to counteract gut dysbiosis‐related thrombogenesis, with resveratrol emerging as a promising candidate for mitigating hypercoagulability and reducing thrombotic risk [115].

MD has been extensively studied for its CV benefits, primarily due to its emphasis on plant‐based foods such as legumes, whole grains, nuts, fruits, vegetables, and extra virgin olive oil. This diet is rich in omega‐3 polyunsaturated fatty acids (PUFAs), which exert antiatherogenic and anti‐inflammatory effects by activating peroxisome proliferator‐activated receptor gamma (PPAR‐γ) and inhibiting nuclear factor kappa B (NF‐κB), thereby reducing the production of pro‐inflammatory cytokines like TNF‐α. As a result, adherence to the MD is associated with a reduced risk of CAD, inflammatory bowel disease, and other chronic inflammatory conditions [119, 120].

Beyond its direct CV benefits, the MD promotes gut microbial diversity. Its high fiber content fosters the growth of Bacteroides species and enhances gut acidification, which supports a balanced microbial ecosystem [120, 121]. Moreover, the fermentation of dietary fibers in the MD produces SCFAs, particularly butyrate, which has been linked to lower rates of CVD and even some cancers [122]. A controlled trial by Kimble et al. demonstrated that MD consumption increases the abundance of Adlercreutzia equolifaciens, a bacterium involved in polyphenol metabolism, and F. prausnitzii, a butyrate‐producing species with potent anti‐inflammatory properties [121–123].

In contrast, WD—characterized by high intakes of saturated fats, refined carbohydrates, sugars, processed foods, and red meats—has been associated with dysbiosis and adverse CV outcomes [121, 122]. Prolonged consumption of WD promotes the secretion of LPS and chylomicron accumulation, fostering an increased abundance of Gram‐negative bacteria such as Alistipes and Bacteroides. This shift compromises intestinal tight junction integrity, facilitating LPS translocation into the bloodstream and triggering systemic inflammation through elevated TNF‐α, interferon‐gamma (IFN‐γ), and IL‐1β. Over time, this chronic inflammatory state contributes to endothelial dysfunction, hypertension, and atherosclerosis [120, 124, 125].

A 3‐year study by Tang et al. found that high dietary phosphatidylcholine—a component abundant in WD—leads to the production of TMAO, a gut‐derived metabolite strongly associated with an increased risk of atherosclerosis [126]. Additionally, the combination of a sedentary lifestyle and excessive consumption of sugar‐sweetened beverages and alcohol further exacerbates gut barrier disruption. A study by Dr. Leclercq on 60 patients demonstrated that alcohol consumption significantly alters gut microbial balance, leading to long‐term cardiac and metabolic dysfunction [127].

Dietary polyphenols, found in plant‐based foods such as fruits, vegetables, tea, cocoa, and wine, have been widely studied for their antioxidant and cardioprotective properties [128, 129]. These compounds enhance gut microbial diversity by promoting the growth of beneficial bacteria like Bifidobacterium and Lactobacillus. Red wine polyphenols, in particular, have been linked to increased levels of Bacteroides, a genus associated with metabolic health benefits [128, 129].

Polyphenol‐rich diets act as prebiotics, fostering the activity of beneficial microbes and improving nutrient absorption [128–130]. Bifidobacterium, a common probiotic, has been shown to support immune function, protect against inflammatory bowel disease, and reduce cancer risk. Additionally, cocoa‐derived polyphenols have been associated with increased high‐density lipoprotein (HDL) levels and reduced plasma triacylglycerol and inflammatory markers [129, 130]. Furthermore, polyphenols exert antibacterial activity against harmful pathogens like Staphylococcus aureus and Salmonella while limiting the growth of pathogenic Clostridium species [130]. Hydroxycinnamic acid, a polyphenol subtype, has demonstrated hepatoprotective, antiobesity, and CV benefits [129–131]. Moreover, flavonoids from polyphenol‐rich foods act as free radical scavengers, reducing blood lipid levels and cholesterol [132].

Physical activity is another crucial modulator of gut microbiota composition. Regular exercise enhances microbial diversity and improves the Bacteroidetes‐to‐Firmicutes ratio, which is linked to better weight management and metabolic health. Exercise promotes the proliferation of beneficial microbes that reinforce gut barrier integrity and mucosal immunity [133].

During exercise, skeletal muscle contractions stimulate the release of myokines, such as interleukin‐6 (IL‐6), which subsequently enhance the secretion of glucagon‐like peptide‐1 (GLP‐1), a key regulator of glucose metabolism [133, 134]. Exercise also increases SCFA production, leading to improved gut integrity, reduced systemic inflammation, and enhanced metabolic function [134, 135]. A randomized controlled trial (RCT) by Zhong et al. demonstrated that aerobic exercise in women significantly improved gut microbiota diversity, with beneficial microbial shifts associated with reduced CV risk factors. Using 16S rRNA sequencing, the study identified increased health‐promoting bacterial genera, reinforcing the connection between physical activity, gut health, and CV well‐being [136].

Probiotics—live microorganisms that confer health benefits—and prebiotics—nondigestible food components that promote the growth of beneficial bacteria—have been extensively studied for their cardioprotective effects. Clinical trials demonstrate their efficacy in modulating CV risk factors. For instance, a trial in patients with type 2 diabetes mellitus (T2DM) found that a 6‐week course of probiotic supplementation significantly reduced blood pressure and the Framingham risk score [137]. Similarly, a meta‐analysis confirmed significant reductions in blood pressure, total cholesterol, LDL‐C, serum glucose, HbA1c, and BMI alongside increased HDL‐C levels [138]. These effects were particularly pronounced with prolonged interventions, higher dosages, and in individuals with metabolic disorders.

The benefits of probiotics are strain‐specific. Strains such as Lactobacillus acidophilus, L. plantarum, L. fermentum, and L. gasseri have demonstrated improvements in blood pressure and lipid profiles. Additionally, L. rhamnosus GR‐1 and Limosilactobacillus reuteri RC‐14 contribute to urogenital health in women, indirectly supporting overall well‐being [139]. Multistrain probiotic formulations often exhibit superior efficacy compared to single‐strain interventions, enhancing CV health outcomes more effectively. Specific strains like Limosilactobacillus reuteri TF‐7, Enterococcus faecium TF‐18, and Bifidobacterium animalis TA‐1 have demonstrated hypocholesterolemic effects, synergistically improving lipid profiles and gut microbiota composition [140, 141]. The mechanisms underlying these benefits include SCFA production, bile salt hydrolase activity, lipid metabolism regulation, and modulation of systemic inflammation, all of which contribute to improved CV health [141].

FMT, the process of transferring gut microbiota from a healthy donor to a recipient, is an emerging intervention primarily used for Clostridioides difficile infections. Its potential in CV health is under investigation. Preclinical studies suggest that FMT can influence atherosclerosis development by modifying gut microbiota composition and reducing systemic inflammation [111]. However, human studies remain limited.

Potential CV benefits of FMT include improved metabolic profiles, modulation of gut‐derived inflammation, and reduction in inflammatory markers associated with metabolic syndrome. Despite its promise, FMT presents several challenges, including limited direct evidence for CV disease, risks of infection transmission, variability in outcomes, and ethical and regulatory concerns. Further research with standardized protocols and large‐scale clinical trials is needed to establish its efficacy and safety for CV applications [142].

Targeting gut microbial metabolites offers another avenue for CV intervention. One of the most well‐researched microbial metabolites is TMAO, which is derived from dietary choline and carnitine metabolism by gut bacteria. Elevated TMAO levels have been linked to atherosclerosis and adverse CV events [143]. Pharmacological strategies to reduce TMAO include [144]1inhibiting TMA production by targeting microbial enzymes responsible for its generation,2blocking the hepatic conversion of TMA to TMAO, and3using nonlethal inhibitors that selectively suppress TMA‐producing pathways without disrupting overall gut microbiota balance.

Reducing TMAO levels has shown promise in lowering CV risk factors, including platelet reactivity and thrombosis risk. Other gut‐derived metabolites, such as SCFAs and bile acids, also play crucial roles in CV health, offering additional therapeutic opportunities through diet, probiotics, and pharmacological agents [144–146].

The gut–heart axis underscores the role of gut microbiota in regulating host metabolism, inflammation, and immune responses. Emerging therapeutic strategies target bacterial metabolites, enhance intestinal barrier function, and modulate inflammatory pathways [147].

Next‐generation probiotics (NGPs), engineered for enhanced stability and targeted disease management, represent a promising advancement in microbiota‐based therapy. The integration of synthetic biology and bioinformatics is facilitating more precise interventions [148, 149]. Future directions include [147–149]•personalized microbiota‐based therapies tailored to individual gut microbiome profiles,•multistrain probiotic formulations optimized for CV benefits,•advanced probiotic delivery systems ensuring greater efficacy, and•combined prebiotic and probiotic interventions to maximize gut microbiota modulation.