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Review

Advancing lifelong precision medicine for cardiovascular diseases through gut microbiota modulation

, & ORCID Icon
Article: 2323237 | Received 19 Dec 2023, Accepted 21 Feb 2024, Published online: 27 Feb 2024

ABSTRACT

The gut microbiome is known as the tenth system of the human body that plays a vital role in the intersection between health and disease. The considerable inter-individual variability in gut microbiota poses both challenges and great prospects in promoting precision medicine in cardiovascular diseases (CVDs). In this review, based on the development, evolution, and influencing factors of gut microbiota in a full life circle, we summarized the recent advances on the characteristic alteration in gut microbiota in CVDs throughout different life stages, and depicted their pathological links in mechanism, as well as the highlight achievements of targeting gut microbiota in CVDs prevention, diagnosis and treatment. Personalized strategies could be tailored according to gut microbiota characteristics in different life stages, including gut microbiota-blood metabolites combined prediction and diagnosis, dietary interventions, lifestyle improvements, probiotic or prebiotic supplements. However, to fulfill the promise of a lifelong cardiovascular health, more mechanism studies should progress from correlation to causality and decipher novel mechanisms linking specific microbes and CVDs. It is also promising to use the burgeoning artificial intelligence and machine learning to target gut microbiota for developing diagnosis system and screening for new therapeutic interventions.

Introduction

The gut microbiota represents a complex ecosystem within the host’s intestinal tract, comprising a diverse array of microorganisms with over 100 trillion viruses, more than 80 genera of fungi, and at least 1,000 bacterial species.Citation1 These communities engage in numerous interactions and exert intricate modulation over the host’s physiological and pathological processes. In recent years, an abundance of evidence has emerged, shedding light on the interplay between the gut microbiota and the host. Since the composition of gut microbiota and its bioactive products vary greatly with age, gender, diet, metabolism and diseases, and an individual’s microbiome may carry over 100 million genes unique to that person,Citation2 it is of great value to seek for more accurate diagnosis strategies and more targeted individualized therapy based on gut microbiota studies.

CVDs impose a substantial societal burden, affecting individuals across various age groups. From congenital heart diseases in the young to ischemic and degenerative heart diseases in the elderly, safeguarding cardiovascular health throughout life requires a comprehensive approach that encompasses risk factor prevention, early detection, effective treatment, and optimized recovery across all stages of life. However, current medical strategies predominantly concentrate on the adult population, lacking the necessary individual specificity.

The gut microbiota acts as a potential endocrine system, generating bioactive metabolites into the circulation and eliciting comprehensive functions on the physiology and pathology of heart. This gut-heart axis is connected by various metabolite communicators, including the trimethylamine/trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFAs), and primary and secondary bile acids (BAs). Depicting a detailed atlas of specific gut microbes and their metabolites in different CVDs is of great importance in developing target therapies. Targeting Streptococcus, Roche, Ruminococcus that generates TMAO has shown great potential in treating atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF). Ruminococcaceae, Roseburia, Faecalibacterium spp. Bifidobacterium and Lactobacillus produce SCFAs and protects CVDs by regulating blood pressure and glucose metabolism. Lactobacilli, Bifidobacteria, Clostridium and Bacteroides produce BAs that control systemic inflammation and prevent HF.Citation3,Citation4 Therefore, exploring disease-specific and population-specific gut-heart axis from the perspective of the gut microbiota offers a promising avenue to advance cardiovascular medicine toward a more precise era.

Our comprehensive review aims to synthesize the latest advancements concerning gut microbiota-associated CVDs throughout different stages of life (). We specifically investigate the dynamic changes in gut microbiota composition, elucidate the underlying pathological mechanisms implicated in CVDs, and explore the potential of targeting the gut microbiota for the prevention, diagnosis, and treatment of these conditions. Furthermore, we identify current knowledge gaps that persist in the field of gut microbiota-CVD research and propose avenues for future inquiry and innovation in this rapidly evolving domain. By fostering a holistic approach that encompasses prevention, diagnosis, treatment, and rehabilitation, our goal is to advance a lifelong paradigm of CVD medicine.

Figure 1. Gut microbiota development and different CVDs in a full life circle.

Upper: gut microbiota development, maturation, aging features and key influencing factors throughout different life stages. Lower: High prevalence CVDs in different life stages. The number of each CVDs literature in Pubmed is shown in gradient colors.
Figure 1. Gut microbiota development and different CVDs in a full life circle.

From birth to infant

Gut microbiota acquisition and development

In the first month of life, shift from predominantly facultative anaerobes, such as Enterobacteriaceae, to anaerobes like Bacteroidaceae, Bifidobacteriaceae, and Clostridium. Subsequently, between 6 and 24 months, the gut microbiota undergoes progressive maturation, with Clostridium emerging as a dominant component. The formation of early childhood gut microbiota is influenced by several factors, including delivery mode, feeding method, gestational age, maternal gut microbiota during late pregnancy and breastfeeding, as well as the introduction of complementary foods.Citation5–7 These factors affecting the early formation of microbiome influence the host nutrition metabolism and the maturity of immune system, the disturbance of which lead to the higher risk of glucose and lipid metabolism disorder and immune disorder in the future.

Delivery represents a crucial event in the acquisition of gut microbiota, as vaginally born infants harbor gut microbiota primarily composed of resident vaginal bacteria like Bifidobacteriaceae, Lactobacillus, and Prevotella spp..Citation8 In contrast, infants delivered via cesarean section exhibit gut microbiota more reminiscent of the maternal extrauterine environment, characterized by microorganisms such as Enterobacter hormaechei/E. cancerogenus, Haemophilus parainfluenzae/H. aegyptius/H. influenzae/H. haemolyticus, Staphylococcus saprophyticus/S. lugdunensis/S. aureus, Streptococcus australis, and Veillonella dispar/V. parvula.Citation9 Furthermore, their gut microbiota exhibits decreased stability, potentially attributed to a higher abundance of pathogenic microorganisms like Enterococcus and Klebsiella spp., which may contribute to the depletion of Bacteroidaceae .Citation10,Citation11 Bacteroidaceae maintains the balance of immune system and inhibits the growth of pathogenic microorganisms,Citation12 the exhaustion of which may potentially contribute to CVD risks in later life.

Breast milk serves as another significant route for the acquisition of gut microbiota.Citation6,Citation13 Beneficial maternal gut bacteria, such as L. gasseri, L. salivarius, Lactobacillus reuteri, L. fermentum, or Bifidobacterium breve, can be transferred to breast milk through mechanisms involving dendritic cells (DCs), thereby acting as a continuous source of gut microbiota for infants.Citation6 Notably, the breastfeeding history during infancy influences the composition of gut microbiota in adulthood, with individuals who were breastfed primarily exhibiting gut microbiota dominated by Bacteroidaceae, while non-breastfed individuals show an increase in Prevotella abundanceCitation14 and formula-fed infants displaying a notable increase in Proteobacteriaceae abundance.Citation11,Citation15 An increased prevalence of Proteobacteria is a potential signature of dysbiosis and indicates higher risk of type 2 diabetes and obesity in the future.Citation16 Upon introduction of solid foods, there is a significant rise in the abundance of bacteria producing butyrate salts, such as Fecal bacilli and Rosebacterium. R. intestinalis regulates the differentiation of anti-inflammatory Tregs in host immune system,Citation17 playing potential role in CVDs. At this particular stage, the key factor influencing gut microbiota becomes diet composition during weaning period.Citation18 The gut microbiota achieves basic stability within the first three years after birth, eventually reaching adult levels.Citation15,Citation19 A stable gut microbiota possesses colonization resistance, which enables it to resist long-term establishment of foreign bacteria.Citation20 Factors influencing the gut microbial community during this stage primarily include dietary composition, emotions, physical activity, medication use, and overall health status, all of which dynamically shape the host’s gut microbiota.Citation21–23

Congenital heart disease and gut microbiota

CVD during the neonatal stage encompass congenital heart defects (CHD), such as atrial septal defects, ventricular septal defects, and tetralogy of Fallot (TOF). The Centers for Disease Control and Prevention (CDC) reports that approximately 1% (around 40,000 cases) of newborns in the United States are affected by CHD annually, with about a quarter of CHD patients suffering from severe congenital heart disease, predominantly cyanotic congenital heart diseases (CCHD).Citation24 Despite limited research on adverse factors impacting fetal cardiac development, a few risk factors, such as pre-pregnancy obesity and pre-pregnancy diabetes, have been identified.Citation25,Citation26 The question arises as to whether the maternal gut microbiota influences fetal cardiac development. Investigations have revealed a notable decrease in the abundance of Bifidobacteriaceae and Lactobacillus within the gut microbiota of mothers with CHD child.Citation27 Bifidobacteriaceae and Lactobacillus are considered potential producers of folate,Citation28 which may play a role in cardiovascular system development,Citation27 thus potentially influencing the occurrence of CHD.

Infants with CCHD are a high-risk population for malnutrition and immune imbalance, and this disease condition significantly affects the early-life evolution and formation of the gut microbiota. Conversely, the early-life gut microbiota serves as a crucial regulatory factor for host metabolism, development, and immunity,Citation29 suggesting that the gut microbiota may be a pivotal factor in the progression and evolution of CHD after birth. Investigations have identified characteristic features in the gut microbiota of CCHD patients, including a depletion of Bifidobacteriaceae and an overgrowth of Enterococcus, which is associated with diverse gene pool remodeling of temperate core viromes such as Siphoviridae .Citation30 Furthermore, another study observed similar characteristics in the gut microbiota of CHD- HF patients compared to CCHD, with a significant increase in Enterococcus abundance and a decrease in Bifidobacteriaceae abundance compared to the control group.Citation31 These findings suggest that when there is severe impairment of cardiac function in young children, the intestines may experience ischemia or congestion, leading to reduced oxygen supply, increased acidity in the intestinal microenvironment,Citation32 and thus leading to distinct alterations in the gut microbiota.

The excessive proliferation of Enterococcus can lead to damage to the intestinal barrier and the initiation of inflammatory reactions, possibly due to the metabolites produced by Enterococcus, such as arachidonic acid (AA) derivatives (including 20-hydroxy-leukotriene B4, leukotriene F4, lipoxin A4, and lipotoxin B4). These metabolites, when the intestinal barrier is compromised, can trigger a series of inflammatory responses in the circulation.Citation33 Furthermore, studies have demonstrated that Enterococcus faecalis can disrupt the function of the intestinal epithelial barrier and induce intestinal inflammation through the secretion of gelatinase (GelE).Citation34 These findings directly relate to the observed intestinal barrier damage and excessive inflammatory response in neonates with CCHD. The characteristic reduction of Bifidobacteriaceae, which are known as producers of SCFAs,Citation35,Citation36 plays a vital role in maintaining internal environmental stability and safeguarding cardiovascular health. Bifidobacteriaceae exert their beneficial effects by promoting the stability of the gut microbiota, exerting anti-inflammatory properties, regulating immune responses, and nourishing the intestinal epithelium.Citation37 Cardiopulmonary bypass (CPB) is a widely used technique in pediatric cardiothoracic surgery. Salomon et al. studied the stool samples of 36 CHD patients undergoing CPB and found that children in CPB group had gut microbiome imbalance (Actinobacteria and Proteobacteria increased significantly) and intestinal barrier function.Citation38 Most patients with major CHD surgery will be treated in intensive care unit (ICU). Some studies have found that 90% of gut microbiome is lost within 6 hours after admission to ICU, which leads to systemic inflammatory reaction and promotes the occurrence of HF. A recent clinical cohort study identified Enterococcus as an independent prognostic indicator for postoperative outcomes in CCHD patients, alongside other predictive indicators such as intraoperative transfusion volume and cardiopulmonary bypass time.Citation30

The significant alterations observed in the gut microbiota of infants with CHD provide a promising avenue for exploring the potential of utilizing the gut microbiota as a diagnostic or predictive tool for HF occurrence or prognosis in CHD patients. It was demonstrated that the gut microbiota-derived metabolite kynurenine could serve as a predictor for the degree of left ventricular remodeling in children with left ventricular pressure overload, exhibiting a negative correlation with cardiac function.Citation39 However, the feasibility of constructing a diagnostic or predictive panel based on the gut microbiota and its metabolites in the CHD population remains uncertain, warranting further comprehensive investigations into gut microbiota profiles with meticulous age, gender, and CHD subtype stratification. These studies should be accompanied by investigations into the underlying mechanisms to establish personalized and CHD subtype-specific approaches for gut microbiota-based diagnostics.

Based on these findings, interventions targeting the gut microbiota present a promising insight for the treatment and prevention of HF in CHD patients. Nonetheless, the current body of evidence and direct mechanistic investigations concerning the benefits of gut microbiota intervention during this critical developmental stage remains insufficient. As for the notable differences in the gut microbiota composition of infants delivered via cesarean section compared to those born vaginally, investigators initially proposed a technique known as “vaginal seeding”, involving the immediate exposure of cesarean-born infants to maternal vaginal fluid, as a potential strategy to rectify the imbalanced gut microbiota in these infants.Citation38 However, disappointingly, studies have indicated that the implementation of vaginal seeding did not yield significant effects on the gut microbiota of cesarean-born infants in the short term (at 3 months) or long term (at 3 years).Citation38,Citation40 Nonetheless, in a recent study involving 32 cesarean-born infants, the application of gauze soaked in maternal vaginal fluid to the infants’ lips, skin, and hands was employed. Remarkably, after six weeks post-birth, the transplanted infants exhibited a higher presence of intestinal bacteria derived from maternal vaginal fluid, thereby resembling the gut microbiota composition of vaginally born infants. Additionally, these transplanted infants displayed a greater abundance of mature bacteria in their gut at six weeks of age, akin to their vaginally born counterparts. Furthermore, at three and six months of age, the transplanted infants exhibited significantly higher scores in neurodevelopment, comparable to those born vaginally.Citation41 This noteworthy discovery raises important questions regarding the potential improvement of cardiac outcomes and prevention of HF in cesarean-born infants with CHD through vaginal microbiota transplantation to rectify their imbalanced gut microbiota.

Moreover, the possibility of directly correcting the imbalanced gut microbiota of newborns through probiotic therapy warrants exploration. Research indicates that the optimal time window for probiotic intervention in cesarean-born infants is within the first three months of life,Citation42 and earlier interventions result in smaller disparities in gut microbiota composition between cesarean-born and vaginally born infants.Citation43 Furthermore, interventions combining Bifidobacteriaceae with Lactobacillus have demonstrated superior effects compared to single-strain interventions.Citation43 The efficacy of probiotic preparations, commonly employing Lactobacillus rhamnosus, Bifidobacterium infantis, Lactobacillus reuteri, and Bifidobacterium lactis, in preventing necrotizing enterocolitis in preterm infants has also been confirmed.Citation43,Citation44 This suggests that early administration of probiotic preparations to modulate the gut microbiota and promote its maturation can effectively maintain intestinal barrier function, reduce inflammation levels, and facilitate immune system development.Citation44,Citation45 Supplementing of Bifidobacterium lactis plus inulinCitation46 for CCHD patients was illustrated to reduce the incidence of necrotizing enterocolitis and mortality by strengthening of the nonimmunologic gut barrier, interference with pathogen adhesion and growth inhibition, and the enhancement of the local mucosal immune system in the gut, as well as of the systemic immune response. Our previous studies have demonstrated that specific probiotic supplementation in newborn mice with coarctation of the aorta improved left ventricular remodeling and delayed the onset of HF by targeting kynurenine-AHR-remodeling pathways.Citation39 The probiotics therapy showed great advantages over synthesized molecular inhibitors targeting kynurenine and its tryptophan metabolism, especially its safety and accessibility. However, further clinical evidence is necessary to establish the potential benefits of probiotic supplementation for CHD patients’ hearts. The major obstacle hindering the development of targeted probiotics in children may still be the instability of their gut microbiome, as there is considerable inter-individual variability influenced by above factors. Nonetheless, investigating other specific gut microbes and their tryptophan metabolites is still intriguing, including indole, indole-3-pyruvic acid, 5-OH-indole-3-acetic acid, which all showed strong CVDs correlation in a recent adult study.Citation47 Similarly, given that breast milk harbors beneficial bacterial species and metabolites derived from the maternal gut, investigating the potential of maternal probiotic supplementation to enhance the structure of breast milk microbiota and promote gut colonization in CHD infants represents a promising point for future research.

Childhood and adolescent

Gut microbiota development and influence factors

Throughout childhood and adolescence, the gut microbiota composition is continuously influenced by factors such as growth, development, and individual lifestyle habits, while reciprocally impacting physiological development.Citation29 Following weaning, a notable decline in Actinobacteria relative abundance occurs in the gut of healthy children, which further decreases with age. During this period, Firmicutes largely characterize the gut microbiota.Citation48 At this stage, Firmicutes establish mutualism with the host via innate tolerance and resistance to control systemic immunity.Citation49 Firmicutes also interact with intestinal fiber digestion to maintain health and prevent the risk of obesity and diabetes. Contrasting adult profiles, healthy Dutch children aged 6–9 exhibit a gut microbiota primarily dominated by Bacteroidaceae, accompanied by a significant increase in Bifidobacteriaceae abundance.Citation50 Conversely, healthy American children aged 7–12 display a higher Firmicutes abundance compared to adults, while Bacteroidaceae abundance decreases.Citation51 These findings emphasize the influence of geographical location and ethnicity on the gut microbiota composition in infants and adolescents. Early breastfeeding duration inversely correlates with Bifidobacteriaceae abundance in the gut of school-aged children.Citation50 Similarly, dietary fiber intake in preschool children negatively correlates with Bifidobacteriaceae abundance.Citation52 Bifidobacteriaceae is found to play a key role in suppressing oxidative stress, improving immunomodulation, and correcting lipid, glucose, and cholesterol metabolism.Citation53 However, whether early breastfeeding or fiber intake has CVDs linkage warrants further invastigations. Dietary habits also modulate the gut microbiota’s development and composition. For instance, vegans exhibit reduced abundance of Bifidobacteriaceae and Bacteroidaceae, leading to decreased microbial diversity, yet without a significant decline in SCFA production.Citation54 In a study involving 6-week-old mice fed a high-sugar diet, there was a decrease in Bacteroidetes abundance and an increase in Proteobacteria abundance in the gut, accompanied by heightened gut permeability.Citation55 The Proteobacteria and its associated gut permeability may increase systemic inflammation and the risk for HF.Citation56 Physical activity habits positively influence the gut microbial community, with exercise promoting the production of butyrate-producing bacteria like Roseburia hominis, Faecalibacterium pausnitzii, and Ruminococcaceae .Citation57 These gut butyrate producers were reported to have potential protection against infarcted heart and ASCVDs.Citation58,Citation59 Collectively, these findings underscore the need to consider factors such as geographical location, ethnicity, early-life acquisition of gut microbes, and lifestyle habits when developing diagnostic or intervention approaches based on the gut microbiota during childhood and adolescence.

Kawasaki disease and gut microbiota

CVDs affecting children and adolescents encompass a range of notable conditions. Kawasaki disease (KD), an acute febrile systemic vasculitis primarily occurring in children, is a major cause of acquired heart disease in this population, often resulting in coronary artery lesions.Citation60 The majority of KD patients (approximately 80%) are under the age of 5. While the precise etiology of KD remains elusive, abnormal immune responses, such as aberrant neutrophil activation, excessive expansion of Th17 cells, depletion of Treg cells, and overproduction of inflammatory factors (e.g., IL-1, IL-2, IL-6, IL-8, and TNF-α), have been implicated in this condition.Citation61 However, emerging evidence suggests that the gut microbiota plays a crucial role in the pathogenesis and progression of KD, along with immune system dysregulation. Initial investigations isolated 13 types of Gram-negative bacteria expressing heat shock protein 60 (HSP-60), a protein capable of inducing monocyte secretion of IL-10, as well as 18 types of Gram-positive bacteria harboring superantigens (SAGs) that can induce expansion of Vβ2+ T cells, from the gut of KD patients.Citation62 These findings imply that the gut microbiota may indirectly influence KD by modulating the immune system. Hu et al. reported dysbiosis in the gut microbiota of KD patients, characterized by a significant reduction in the abundance of Bacteroidaceae, Lachnospiracea_incertae_sedis, and Blautia, accompanied by an increase in the abundance of Escherichia_Shigela, Bifidobacteriaceae, and Enterococcus genera, in comparison to the control group.Citation63 Other studies have observed a marked decrease in fecal Bacilli and Roseburia abundance, which are known producers of SCFAs, during the acute phase of KD.Citation64 Notably, these taxa that experience reduced abundance are known to produce SCFAs, with Bacteroidaceae and Blautia producing acetate, fecal Bacilli and Roseburia generating butyrate,Citation65 and Lachnospiraceae producing both acetate and butyrate.Citation66 Moreover, SCFAs exert regulatory influences on glucose and lipid metabolism, blood pressure regulation, and immune modulation by engaging signaling pathways involving G protein-coupled receptors 41 (GPR-41), GPR-43, and olfactory receptor 78 (Olfr-78), as well as by inhibiting histone deacetylases (HDAC) Citation67 and the nuclear factor kappa B (NF-κB) pathway, thereby contributing to overall health.Citation68 These findings might suggest a potential significant role of SCFAs in the onset and progression of KD. To validate the involvement of the gut microbiota and its metabolite SCFAs in KD, Wang et al. established a mouse model of KD using a water-soluble component of Candida albicans and observed a reduction in SCFA-producing bacteria in the gut of KD model mice, accompanied by compromised intestinal barrier function and exacerbated inflammatory responses in KD.Citation60 However, when supplemented with butyrate-producing bacteria, the mice demonstrated alleviated intestinal barrier damage. Subsequent experiments involving butyrate supplementation in KD mice revealed decreased circulating levels of IL-6 and TNF-α and reduced inflammatory cell infiltration in the coronary arteries, implying a beneficial role of the gut microbiota-derived metabolite, butyrate, in KD. Kazunari et al. introduced the concept of “ecological imbalance” in KD,Citation69 proposing that pre- and postnatal factors (including maternal gut microbiota composition, vaginal infections, periodontal disease, cesarean section, formula feeding, and excessive antibiotic usage) contribute to dysbiosis in the gut microbiota of young children, characterized by a significant decline in SCFA-producing microorganisms, consequently disrupting the balance between Th17 and Treg cells. Subsequent infection triggers hypercytokinemia, also known as a cytokine storm, and initiates KD. This perspective underscores the significance of the gut microbiota in KD and identifies the reduction of SCFAs as a pathogenic mechanism, thus offering novel insights for the prevention and treatment of KD.

Promising future research directions involve the development of diagnostic panels based on the gut microbiota and its metabolic products to predict coronary events. However, it is essential to acknowledge that while these studies provide valuable insights into the potential involvement of the gut microbiota and SCFAs in KD, the clinical evidence for interventions targeting the gut microbiota or SCFA supplementation remains limited. Further investigation is warranted to gain a deeper understanding of the underlying mechanisms and to assess the efficacy of such interventions in the prevention and treatment of KD.

Type 1 diabetes mellitus and gut microbiota

Type 1 diabetes mellitus (T1DM) represents the most prevalent chronic autoimmune ailment afflicting children, with its highest incidence observed during the ages of 5–7 and adolescence or near adolescence.Citation70 T1DM is acknowledged as a significant risk factor for cardiovascular health, and as the lifespan of individuals with T1DM increases, their susceptibility to cardiovascular events escalates tenfold compared to non-diabetic counterparts of similar age.Citation70 Recently, studies have unveiled the pivotal role played by the gut microbiota in T1DM development, rendering it an innovative therapeutic target. The “TEDDY” study discovered that children exhibiting augmented abundance of Bifidobacteriaceae and diminished levels of Streptococcus thermophilus and Lactococcus lactis in their gut microbiota were predisposed to T1DM prior to its onset.Citation71 Comparative analysis between T1DM children and their healthy counterparts has revealed distinct compositional alterations in the gut microbiome. At the phylum level, Actinobacteria and Firmicutes demonstrated reduced levels in T1DM children, while Bacteroidaceae exhibited increased abundance. Furthermore, at the genus level, T1DM children exhibited significant decreases in Lactobacillus, Bifidobacterium, Blautia coccoides/Eubacterium rectale group, and Prevotella, whereas Clostridium, Bacteroides, and Veillonella displayed noteworthy increases.Citation70,Citation72 A comprehensive summary of the dysbiotic traits in T1DM gut microbiota by Yuan et al.Citation73 outlined a decline in butyrate-producing bacteria within the Firmicutes phylum, including Faecalibacterium, Blautia, Lachnospira, Ruminococcus 2, and Roseburia, alongside an elevation in Bacteroides, Parabacteroides, and Escherichia Shigella. This dysbiosis of the gut microbiota induces functional disruptions such as reduced butyrate production, heightened lipopolysaccharide (LPS) synthesis, and impaired BAs and carbohydrate metabolism. LPS, a principal constituent of gram-negative bacteria, has the capacity to directly trigger inflammation by binding to Toll-like receptor 4 (TLR4),Citation74 thereby further aggravating immune system dysregulation in the host. Mouse models have further substantiated that diminished butyrate production and increased LPS synthesis facilitate the progression of T1DM.Citation73 The decrease of circulating SCFAs and increase of LPS would lead to chronic endothelial inflammation, which is associated with higher risks of HTN and ACSVD. Clinical trials encompassing fecal microbiota transplantation (FMT) from healthy individuals to newly diagnosed (<6 weeks) T1DM patients have demonstrated the preservation of residual beta cell function and the cessation of endogenous insulin level decline subsequent to FMT intervention.Citation75 This FMT increased Desulfovibrio piger abundance and prevented the progression of T1DM by its metabolite 1-myristoyl-2-arachidonoyl-GPC that regulated T cell autoimmunity. These findings suggest that early rectification of gut microbiota dysbiosis may delay, prevent, or even reverse the advancement of T1DM. Moreover, identifying early alteration of T1DM gut microbiota provides possible recognition of this certain population.

Residue CHD problems and gut microbiota

Within the pediatric population, special attention should be given to a subset of postoperative children with CHD. While surgical interventions for simple CHD have achieved remarkable therapeutic efficacy, long-term mortality rates following surgery for left heart-related CHD, particularly mitral valve disease, have surpassed those of CCHD such as TOF, emerging as the leading cause of sudden death in adolescents and profoundly impacting the long-term quality of life for CHD-affected children.Citation76 CHD associated with increased pressure/volume overload are highly prone to ventricular remodeling, culminating in HF. Surgical correction remains the optimal approach to alleviate obstruction or shunt closure for these pediatric cases; however, residual stenosis and residual shunt post-surgery are not uncommon, exacerbating the gradual progression of ventricular remodeling. Failure to promptly detect and intervene in ventricular remodeling can lead to irreversible myocardial hypertrophy and interstitial fibrosis, significantly heightening the risks of HF and surgery, thereby deteriorating long-term outcomes. To ensure lifelong health for children with CHD, it is imperative to identify, diagnose, and intervene in ventricular remodeling early in adolescence. While research on cardiac risk assessment after CHD surgery primarily focuses on preoperative and intraoperative factors (preoperative age, weight, surgery duration, cardiopulmonary bypass time, aortic cross-clamp time, etc.),Citation77 investigations into postoperative prediction remain relatively scarce. The gut microbiota possesses potent regulatory and nutritional modulation capabilities, potentially exerting a crucial role in postoperative cardiac functional changes in children with CHD. However, studies investigating alterations in the gut microbiota following CHD surgery are limited, warranting further exploration to elucidate the involvement of gut microbial communities in the context of postoperative CHD.

Modulating gut microbiota also have shown promising effect on protecting the heart from adverse remodeling under these mild but chronic hemodynamic changes. Carrillo-Salinas et al. discovered that gut microbiota depletion by antibiotics cocktail (ABX) protect the mice from transverse aortic constriction (TAC) induced remodeling, which was associated with reduced activated T cell.Citation78 Lin et al. found that transplanted of healthy gut microbiota to TAC mice help to reduce fibrosis and prevent further decline of cardiac functions, which was achieved by gut microbiota derived acetate and propionate.Citation79 However, there are still lack of animal models that stimulate CHD postoperative situation and its long-term effect, and more gut microbiota-based study would be noteworthy to develop new therapeutical target for these particular population. Early recognition of specific gut dysbiosis and long-term surveillance of gut microbiome composition hold great promise in adverse event prediction and early intervention for these population.

Adult

Gut microbiota in adult

During the adult lifespan, spanning approximately 18 to 40 years, the gut microbiota undergoes a phase of notable stability, characterized by a delicate equilibrium with subtle fluctuations.Citation80 Notably, the diversity of gut bacteria exhibits a positive correlation with age, with females displaying greater diversity than males, although this correlation diminishes beyond the age of 45.Citation81 Within the adult gut microbiota, the dominant phyla observed are Firmicutes and Bacteroidaceae, accounting for a substantial 95% of the overall bacterial population. The Firmicutes/Bacteroidetes ratio could generally indicate the hemostasis of both gut and the host, the increase of which is closely correlated with metabolic disorders, especially seen in obesity, type 2 diabetes mellitus (T2DM) and ASCVD.Citation82 The composition of the gut microbiota is significantly influenced by long-term dietary habits, whereby diets rich in protein and animal fats are associated with a higher abundance of Bacteroidaceae, whereas carbohydrate-based diets are linked to an increased prevalence of Prevotella spp.Citation83 Prevotella was also found to be associated with HTN.Citation84 Moreover, the presence of chronic diseases in the host exerts an impact on the gut microbiota composition. For instance, patients afflicted with inflammatory bowel disease exhibit a decrease in the abundance of Firmicutes capable of producing SCFAs,Citation85,Citation86 while obese individuals demonstrate an elevated Firmicutes/Bacteroidaceae ratio in their gut microbiota composition.Citation82 The host’s psychological state also interacts with the gut microbiota through the intricate brain-gut-microbiota axis. Notably, patients experiencing severe depression exhibit a decline in the abundance of Actinobacteria and a reduction in Bacteroidaceae abundance within their gut microbiota.Citation87 Thus, while the gut microbiota of adults maintains relative stability, investigations into gut microbiota-related CVDs during adulthood should still take these distinct individual and personalized characteristics into consideration. The application of diagnostic and intervention approaches based on the gut microbiota cannot be universally generalized across diverse diseases or populations, necessitating comprehensive consideration of the aforementioned multiple factors influencing gut bacteria. Nevertheless, the recognition of these complexities also offers prospects for the development of diagnostic and intervention methods predicated on the gut microbiota that align more closely with the principles of precision medicine.

Tobacco use and gut microbiota

Tobacco use represents a prominent risk factor for CVD, contributing to 30% of CVD-related mortality.Citation88 In China, the smoking rate among individuals aged 15 and above reached 26.6% in 2018, accounting for over 300 million smokers. Emerging evidence suggests that tobacco use exerts an influence on the composition of the gut microbiota.Citation89 Notably, among tobacco users, a marked reduction in the abundance of Bifidobacteriaceae and Lactobacilli in the gut microbiota has been observed,Citation90,Citation91 while the enrichment of Eggerthella lent, a member of Actinobacteria, has been noted.Citation91 The reduction of Bifidobacteriaceae and Lactobacilli was reported to hamper the production of SCFAs but increase plasma TMAO, and thus increasing the risk of HTN and ASCVD. However, the cessation of smoking, even in the short term, can lead to a certain degree of recovery in the gut microbiota composition especially the abundance of Bifidobacterium .Citation90 Bifidobacterium is known to efficiently produce SCFAs, which restores the gut-dependent blood pressure regulation capacity and inhibits oxidative stress of vascular endothelium. Particularly noteworthy is the ability of Eggerthella lent to promote the production of BAs metabolites, specifically taurodeoxycholic acid (TDCA), which activates the mitogen-activated protein kinase (MAPK) pathway, disrupts intestinal barrier integrity, and elicits inflammatory responses.Citation91 Moreover, the gut microbiota could influence reward responses associated with smoking through the microbiota-gut-brain-smoking axis,Citation92 further study showed that gut microbiota depletion enhanced the response to nicotine of dopaminergic neurons of the posterior ventral tegmental area (pVTA), and altered nicotine’s rewarding and aversive effects. Thereby rendering the gut microbiota, a potential target for therapeutic interventions in smoking cessation.Citation93 Other mouse experiments have found that exposure to nicotine in early life could lead to decreasing of Bacteroides and increasing of Firmicutes, Actinobacteria, and Proteobacteria. This led to a decrease in the ability of the gut to produce SCFAs and an increase in vagus nerve excitability, resulting in an increased incidence of obesity.Citation94 At the same time, the decrease in the abundance of Bacteroidetes and the ability to produce SCFAs in the intestine damage the intestinal barrier and increase the incidence of ASCVD and HF through intestinal dependent blood pressure regulation. Thus, it seems that targeting specific gut microbes not only blocks tobacco addiction through gut-brain axis, but also shows great benefits in cardiovascular health via gut-heart axis. Recent investigations have revealed that Bacteroides xylanisolvens, functions as a nicotine-degrading agent by metabolizing nicotine into 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB), thereby blocking the nicotine-nicotinamide adenine dinucleotide (NAD) pathway.Citation95 NAD disrupts lipid metabolism, leading to insulin resistance, dyslipidemia, metabolic dysfunction, and cell death,Citation96 exerting detrimental effects in conditions such as ASCVD, T2DM, and HF.Citation97,Citation98 It appears that Bacteroides xylanisolvens within the gut microbiota may play a beneficial role in the development of CVD among smokers; however, further research is warranted to elucidate the bioactivity of its metabolite HPB. Modulating the gut microbiota and reversing the changes caused by smoking provide possible protection in cardiac functions for these group of patients.

Obesity and gut microbiota

The association between overweight and obesity with CVD, particularly ASCVD, in adults is becoming increasingly apparent.Citation99 Obese individuals display distinct alterations in the gut microbiota,Citation82 characterized by a marked reduction in the abundance of Akkermansia, Faecalibacterium, Oscillibacter, and Alistipes bacteria.Citation100 The reduction of Akkermansia was reported to be associated with intestinal barrier interruption and increased circulating inflammation factors,Citation101 which largely increased the risk of ASCVD in obesity. The “obese-type” gut microbiota fosters energy absorption, thereby contributing to obesity. Notably, single nucleotide polymorphisms (SNPs) associated with BMI is located in a non-synonymous polymorphism within the Faecalibacter prausnitzii_G (Rep_3066) genome.Citation102 F prausnitzii-derived butyrate attenuates chronic kidney disease through its G protein-coupled receptor (GPR) signaling pathway.Citation103 However, Fusimonas intestini (FI) has been identified as highly prevalent in populations affected by obesity and diabetes. Further investigation in germ-free mice colonized by FI have demonstrated that FI exacerbates lipid metabolism disorders through the production of metabolites such as trans-unsaturated fatty acids and lipid metabolites, leading to interrupted intestinal barrier and endotoxemia and thus promoting cardiovascular risks.Citation104

Interventions targeting the gut microbiota to ameliorate obesity present a significant strategy in the prevention of obesity-related CVDs. Metabolites derived from the gut microbiota, such as SCFAs, elicit the secretion of intestinal hormones including glucagon-like peptide-1 (GLP-1), while concurrently suppressing the release of ghrelin, thereby effectively suppressing appetite.Citation105 GLP1R signaling has also shown great potential in protecting the heart and blood vessels in the recent years,Citation106 giving promise in regulating gut microbiota-GLP1 axis. Additionally, investigations conducted in germ-free mice colonized by Lactobacillus paracasei have demonstrated that this specific bacterium induces the expression of ANGPTL4, a pivotal regulator of fat storage, thereby preventing diet-induced obesity in the colonized mice.Citation107 ANGPTL4 has also shown protective effect in coronary heart disease and infarcted heart repair,Citation108,Citation109 suggesting Lactobacillus paracasei as potential new target. Another study found that prebiotic oligofructose (OFS) quickly increased the relative abundance of Bifidobacterium in the small intestine and improved its lipid sensing mechanism to restore normal appetite through the gut-brain axis.Citation110 Ligilactobacillus murinus, as a probiotic supplement, upregulated the expression of peroxisome proliferator-activated receptor γ (PPAR-γ) in intestinal epithelial cells to alleviate lipid metabolism turbulence.Citation111 This indicated that the obesity could be intervened in early life and would exert persistent effect lifelong. Future classification of “Obese-type” and “non-obese type” gut microbiota provides more precise intervention for certain group of patients. Provided that gut microbiota in early life stage participates in host’s lipid metabolism, modulation of gut microbiota in early life (before 3 years old when gut microbiota is under development) could also possibly prevent the occurrence of adult obesity and associated CVDs.

Myocarditis and gut microbiota

Myocarditis, characterized by inflammatory cell infiltration and cardiac function deterioration, is an inflammatory disease that can progress to fatal cardiomyopathy. The onset of myocarditis typically occurs between the ages of 30 and 45, with a higher incidence among males. Within the age group of 35–39 years, there are 6.1 myocarditis cases per 100,000 males, with a mortality rate of 1 in 72.Citation112 Excessive immune system activation plays a crucial role in the occurrence and development of myocarditis, and the gut microbiota exhibits significant potential and robust immunomodulatory capabilities. Therefore, the gut microbiota may serve as a significant influencing factor in the occurrence and progression of myocarditis, representing a potential therapeutic target.

In a study investigating experimental autoimmune myocarditis (EAM) in mice, it was observed that the gut microbiota of the EAM group exhibited a significantly increased Firmicutes/Bacteroidaceae ratio compared to normal mice. Specifically, the abundance of Ruminococcus and Lachnobacterium at the genus level was found to be elevated in EAM mice.Citation113 Genetic predictions conducted by Luo et al. revealed that each unit increase in Shigella concentration in the gut microbiota corresponded to a 38.1% relative risk increase for myocarditis.Citation114 These findings suggest a potential role of gut microbiota dysbiosis in myocarditis. Notably, a crucial factor in the pathological changes of myocarditis is the abnormal induction of myosin heavy chain 6 (MYH6), triggering an autoimmune response. The specific targeting of MYH6 by Th1 and Th17 cells results in inflammatory cardiomyopathy.Citation115,Citation116 Individuals with genetic susceptibility who exhibit an immune system that abnormally targets MYH6 may have a significant association with mimic antigens of Bacteroidaceae in the gut. Cross-reactive CD4+ T cells in the gut can infiltrate myocardial cells and exacerbate myocardial damage, which is also a critical pathological process in immune checkpoint inhibitor-induced myocarditis.Citation116 Therefore, the administration of antibiotics to genetically susceptible patients receiving immune checkpoint inhibitors may potentially prevent myocarditis.Citation116 However, antibiotics could interfere with the efficacy of immune checkpoint inhibitors, and thus a targeted eradication approach of Bacteroidaceae with mimic antigens through phage therapy was proposed.Citation117 Moreover, Hu et al. performed Fecal Microbiota Transplantation (FMT) therapy on mice with EAM induced by mouse α-myosin heavy chain and observed a reduction in the Firmicutes/Bacteroidaceae ratio in the mouse gut, leading to the restoration of gut microbiota and subsequent alleviation of myocardial injury. This effect was associated with an increase in the relative abundance of Bacteroidaceae producing SCFAs.Citation113 In conclusion, interventions targeting the composition and function of the gut microbiota through various approaches hold promise as potential therapeutic strategies for adult myocarditis.

Middle aged

Gut microbiota in the middle-aged CVDs

In the middle age range (45–59 years), a gradual decline in physical health occurs, accompanied by a notable increase in risk factors for CVD, including alcohol consumption, T2DM, and hypertension (HTN). Furthermore, this age group exhibits a high prevalence of valvular heart disease. Although the composition of the human gut microbiota does not undergo significant changes during this stage and remains dominated by Firmicutes, Bacteroidaceae, and Actinobacteria48, an extensive body of literature over the past decade has emphasized the critical regulatory role of the gut microbiota in CVDs and their associated risk factors during this particular period of life.

Alcohol abuse and gut microbiota

The age group of 45–54 years exhibits the highest rates of alcohol consumption and excessive drinking. A J-shaped relationship has been observed between alcohol intake and the risk of CVD, whereby lower and moderate alcohol intake is associated with a decreased risk of CVD incidence and mortality.Citation118 However, heavy drinking significantly increases the incidence and mortality of CVD.Citation119 Recent investigations have unveiled distinctive characteristics in the gut microbiota of individuals with long-term alcohol consumption. These characteristics encompass a reduction in the abundance of Bacteroidaceae and Lactobacillus, along with an elevation in Proteobacteria.Citation120 These changes disrupt the gut microbiota-derived SCFAs production and indicate the loss of cardiovascular protection from the gut. Ethanol, both through its chemical properties and the oxidative byproduct acetaldehyde, can disrupt the integrity of the intestinal mucosal layer and heighten intestinal permeability.Citation121 This disruption gives rise to dysbiosis characterized by an overgrowth of Gram-negative bacteria within the gut microbiota, translocation of LPS into the bloodstream, and ensuing endotoxemia, thereby significantly augmenting the risk of HTN, ASCVD, and other CVDs.Citation122 Moreover, research has indicated a negative correlation between alcohol dependence and the levels of butyrate-producing Clostridium, leading to impairment in glucose and lipid metabolism.Citation123 During chronic alcohol intake, there is an upregulation of host gene expression associated with BAs synthesis and efflux transporters,Citation124 and elevated levels of deoxycholic acid hinder the beneficial bacteria of Bacteroidaceae and Firmicutes, resulting in impaired lipid metabolism and impaired functioning of the intestinal mucosal immune system.Citation125 In summary, the dysbiosis of the gut microbiota induced by long-term alcohol consumption significantly heightens the risk of HTN, T2DM, ASCVD, and other diseases by perturbing host lipid metabolism, diminishing SCFA production, and inducing damage to the intestinal barrier.

Lactobacillus emerges as a potential therapeutic target for mitigating the deleterious consequences of alcohol on the gut. Probiotics, specifically Lactobacillus GG, have demonstrated efficacy in preventing or reversing colonic dysbiosis in mice exposed to chronic alcohol consumption by increasing intestinal FXR – FGF‐15 signaling pathway – mediated suppression of BA de novo synthesis and enhances BA excretion, thereby diminishing systemic inflammation levels.Citation126 Consequently, this effect contributes to a reduced susceptibility to CVD characterized by chronic inflammation as a primary pathological feature. Future research is worthwhile to investigate the gut microbiota in these population and to develop CVDs risk stratification.

Hypertension and gut microbiota

In the realm of CVD prevention and treatment, the management of HTN assumes paramount significance. Notably, the prevalence of HTN escalates with advancing age, with the age group of 35–64 demonstrating the most rapid surge in HTN occurrence.Citation127 The pivotal involvement of the gut microbiota in blood pressure regulation has garnered significant recognition, to the extent that studies have even demonstrated the “transmission” of HTN through the transplantation of gut microbiota from hypertensive patients into germ-free mice.Citation84

Investigations have unveiled distinctive features in the gut microbiota of individuals with HTN, characterized by a decline in the abundance of SCFA-producing species, such as Bifidobacteriaceae, concomitant with an increase in the abundance of potentially pathogenic bacteria, including Klebsiella, Streptococcus, and Parabacteroides.Citation128 Furthermore, a noteworthy reduction in the levels of SCFAs, notably butyrate, has been observed in the feces of HTN patients.Citation129 SCFAs assume a pivotal role as signaling molecules implicated in blood pressure regulation, attenuation of circulating inflammatory mediators, and modulation of the renin-angiotensin system (RAS) pathway.Citation68

Trimethylamine N-oxide (TMAO), a metabolite originating from choline and produced by the gut microbiota, particularly Clostridium XIVa ,Citation130 undergoes hepatic oxidation and is implicated in exerting considerable detrimental effects on cardiovascular health.Citation131 Meta-analytical findings have unveiled a dose-dependent association between circulating TMAO levels and the occurrence of HTN.Citation132 Subsequent investigations have provided evidence that TMAO facilitates the development of HTN by augmenting angiotensin II (Ang II)-induced vasoconstriction.Citation128,Citation133

BAs, initially synthesized in the liver, undergo modifications by the gut microbiota, including Lactobacillus, Bifidobacteriaceae, Clostridium, and Bacteroidaceae,Citation4,Citation134 resulting in the formation of diverse BA types. Possessing inherent antibacterial properties, BAs can reduce circulating inflammatory factors by modulating gut microbiota homeostasis and intestinal immunity.Citation135 They play a beneficial role in cardiovascular health, as they bind to the farnesoid X receptor (FXR),Citation136 thereby promoting the production of nitric oxide (NO) and inhibiting the production of endothelin-1 (ET-1), effectively acting as endogenous vasodilators and exerting a positive influence on blood pressure regulation.Citation137

To these end, gut microbiota could be a potential target treating HTN, sometimes even by simple diet improvement. Marques et al. illustrated high fiber diet and acetate supplement could effectively reconstruct gut microbiota and increase the abundance of acetate-producing Bacteroides acidifaciens, significantly reduced both systolic and diastolic pressure in mineralocorticoid induced HTN mice by the downregulation of cardiac and renal Egr1 (a master cardiovascular regulator involved in cardiac hypertrophy, cardiorenal fibrosis, and inflammation).Citation138 Zhang et al. validated lactulose supplement increased the abundance of Bifidobacterium, Alloprevotella, and Subdoligranulum, which neutralized the devastating effect of high salt diet on blood pressure by increasing gut microbiota-derived indoles, thereby decreasing circulation inflammatory cytokines.Citation139 Research also demonstrated chlorogenic acid could enhance the production of BAs, especially deoxycholic acid, via increasing the abundance of Klebsiella oxytoca, which help to improve the blood pressure in high-fructose-induced salt-sensitive mice.Citation140 More and deeper investigations could largely promote clinical translation of gut microbiota-based therapy in treating HTN.

Type 2 diabetes mellitus and gut microbiota

T2DM represents a progressive metabolic disorder characterized by peripheral insulin resistance and impaired pancreatic β-cell function, culminating in disruptions in glucose metabolism and the persistence of chronic low-grade inflammation. Notably, it constitutes a prominent risk factor for cardiovascular well-being.Citation141 Compelling evidence has accumulated regarding the dysbiosis of gut microbiota in patients with T2DM. Specifically, the abundance of Lactobacillus displays a positive correlation with fasting blood glucose (FBG) and glycated hemoglobin (HbA1c), while Clostridium exhibits a negative correlation with FBG, HbA1c, and plasma triglyceride levels.Citation142 This indicated that gut microbiota not only participated in glycolipid absorption in gut, but also greatly involved in glycolipid metabolism in host.

The gut microbiota exerts its influence on the development of T2DM through its intricate association with metabolites. Propionic acid imidazole (ImP), a metabolic byproduct of the gut microbiota species Eggerthella lenta and Streptococcus mutans, directly triggers insulin resistance (IR) via the mTORC1-p38γ signaling pathway.Citation143 The reduction of SCFAs producing microbes, such as Bifidobacteriaceae, Roseburia intestinalis and Faecalibacterium prausnitzii, suggests the loss of gut-dependent cardiovascular protection, leading to increasing risk of HTN and ASCVD in T2DM patients. SCFAs originating from gut bacteria stimulate GLP-1 expression in intestinal enteroendocrine cells through the activation of GPR41 and GPR43 receptors, thereby enhancing glucose metabolism, promoting pancreatic β-cell differentiation, and facilitating the restoration of FBG and HbA1c levels.Citation144–146 Additionally, BAs of gut microbial origin activate FXR, resulting in increased GLP-1 expression and improved glucose metabolism.Citation146 The loss of such GLP-1 protection was reported to be closely related to HF events and cardiovascular mortality in T2DM patients,Citation147 highlighting the role of gut microbiota in the relationship between T2DM and CVDs. Gut microbiota-derived TMAO fosters systemic inflammation by impeding NLRP3 inflammasome activation, stimulating the NF-κB pathway, and suppressing interleukin-10 (an anti-inflammatory cytokine) in T2DM,Citation148,Citation149 which is a significant pathological foundation for ASCVD development. Therefore, targeting TMAO and its associated chronic inflammation also presents as potential treatment strategies for preventing CVDs event in T2DM population. Moreover, gut microbiota metabolites BAs hinder Th17 activity and the secretion of interleukin-17 (a pro-inflammatory cytokine) to mitigate inflammatory disorders in T2DM.Citation150,Citation151

The modulation of the gut microbiota represents a promising therapeutic target for addressing T2DM, offering sustained intervention, convenience, and cost-effectiveness throughout the chronic disease course. Probiotics have exhibited favorable effects on IR in animal models of diabetes.Citation152 Notably, in mice with a HFD and streptozotocin (STZ)-induced diabetes, the administration of Lactobacillus plantarum CCFM0236 resulted in improved IR, reduced levels of circulating inflammation, and alleviated dysfunction of pancreatic β-cell. Further research has found that this effect is related to inhibiting α-glucosidase activity.Citation153 Similarly, treatment with fermented Lactobacillus acidophilus MTCC 5689 demonstrated the amelioration of insulin resistance in HFD-induced diabetic mice and a preventive effect against the onset of diabetes.Citation154 This effect may be related to the increase in SCFAs produced by Lactobacillus acidophilus MTCC 5689.

Valvular heart disease and gut microbiota

Valvular heart disease has emerged as a rapidly growing global health concern, characterized by escalating incidence and mortality rates. Notable forms of valvular heart disease encompass rheumatic heart disease (RHD), aortic stenosis (AS), aortic regurgitation (AR), mitral regurgitation (MR). Infective endocarditis (IE) predominantly involves the valves and are classified within the spectrum of valvular heart disease. AS, in particular, prevails as the most prevalent valve disorder in developed nations, with its incidence rising in correlation with advancing age, particularly among individuals aged 60 and above. RHD persists as the foremost cause of valvular heart disease across the globe, with a higher prevalence observed in developing countries.Citation155 In China, RHD accounts for 55.1% of all valvular heart disease cases and is more frequently encountered in individuals aged 55 and above. Despite advancements, the diagnosis and treatment of various valvular heart diseases necessitate further optimization, and the gut microbiota represents a potential target for preventive and alleviative strategies in these conditions.

AS represents a prevailing degenerative valvular disorder with potentially fatal consequences. Once symptomatic, the disease exhibits relentless progression, resulting in an unfavorable prognosis. Presently, no pharmacological interventions exist to modify the disease trajectory, with aortic valve replacement surgery serving as the sole viable treatment option, albeit unsuitable for all patients.Citation156 Investigations have unveiled a correlation between the pathological and physiological response of AS, specifically the osteogenic reaction of valvular interstitial cells, and the inflammation and immune response elicited by LPS stimulation originating from gut microbial products,Citation157 thus indicating the potential involvement of the gut microbiota in AS development. Notably, studies have identified heightened serum levels of TMAO in AS patients, with these levels associated with adverse outcomes subsequent to aortic valve replacement surgery.Citation158 Within the gut environment, choline and betaine can be metabolized by the gut microbiota into TMAO. Kocyigit et al. demonstrated a correlation between plasma choline levels and the severity of AS, while no significant association was observed between betaine, TMAO levels, and AS severity.Citation159 Further investigations are warranted to elucidate the mechanisms through which products in the TMAO metabolic pathway and LPS influence the occurrence and progression of AS, as the current body of research in this domain remains limited.

The advancement of heart valve disease culminates in cardiac remodeling and HF. TMAO, a metabolite derived from the gut microbiota, fosters the development of HF and triggers myocardial hypertrophy. Clinical investigations have unveiled that supplementation of beneficial bacteria, encompassing Bifidobacteriaceae and Lactobacillus, in HF patients imparts mitigating effects on cardiac remodeling and enhances prognosis.Citation160 The protective effects by these probiotics are diverse, including anti-inflammation, anti-oxidation, and cardiac metabolic reprogramming. Moreover, following probiotic intervention, the intestinal levels of TMAO in patients diminish, thereby indirectly ameliorating cardiac remodeling.Citation161

RHD represents a severe and enduring complication arising from acute rheumatic fever, resulting from autoimmune consequences of mucosal infections caused by group A Streptococcus. While the precise pathogenesis of RHD remains incompletely elucidated, it primarily involves antigen mimicry by group A Streptococcus and dysregulated immune responses in the host.Citation162 RHD stands as a prominent cause of cardiovascular mortality in non-elderly populations worldwide, with limited therapeutic alternatives and potential lifelong antibiotic prophylaxis for patients.Citation163 Consequently, novel strategies are imperative for the control and prevention of RHD. Investigations have unveiled notable alterations in the gut microbiota of RHD patients, including a significant decrease in the relative abundance of Fecal bacilli and Bacteroidaceae, alongside an increase in the relative abundance of Shigella, Gemmiger, Bifidobacteriaceae, Ruminococcaceae, Streptococcus, and Dorea. Moreover, further explorations have demonstrated a negative correlation between Bacteroidaceae and Eubacterium and left atrial diameter (a metric indicative of mitral valve involvement in RHD patients), as well as a negative correlation between Blautia and pulmonary artery systolic pressure (PASP).Citation164 Eubacterium, Bifidobacteriaceae, Fecal bacilli, and Bacteroidaceae hold significance as producers of SCFAs; however, this alone does not wholly elucidate the intricate relationship between the gut microbiota and RHD. Further investigations are warranted to unravel the connection.

The elderly

Gut microbiota in the elderly population

Among the elderly population aged 65 and above, prevalent CVDs encompass ASCVD, atrial fibrillation (AF), and HF. Notably, CVDs have emerged as the foremost cause of morbidity and mortality in this age group, leading to a staggering 40% mortality rate and a substantial surge in healthcare expenditures.Citation165,Citation166 Gut microbiota of older individuals experiences a process of “aging” in tandem with the host’s gastrointestinal tract. Studies have demonstrated a decline in intestinal mucins with age in mice, leading to a thinner and fragmented mucus layer. This mucus layer fulfills a protective role in the gastrointestinal tract and serves as a nutritional substrate for various bacterial strains, including Clostridium, Bifidobacteriaceae, and Bacteroidaceae, which exhibit age-related alterations.Citation80 Badal et al. identified increased levels of Akkermansia and reduced levels of Fecal bacilli, Bacteroidaceae, and Lachnospiraceae with advancing age. Functionally, these microbial changes contribute to diminished carbohydrate metabolism and amino acid synthesis in older individuals.Citation167 These changes indicate the impaired ability of aging gut microbiota to produce SCFAs and BAs, leading to interrupted intestinal barrier and increased risk of CVDs, especially HTN and HF.

Chronic kidney disease and gut microbiota

Chronic kidney disease (CKD), which afflicts 15–20% of adults worldwide, represents an established risk factor for CVD.Citation168 Presently, therapeutic approaches for CKD primarily encompass pharmacological interventions and renal replacement therapy, with no effective means to reverse kidney fibrosis and reinstate renal function in CKD patients.Citation169 Investigation into the gut microbiota of CKD patients has unveiled significant perturbations, underscoring the potential of gut microbiota modulation as an innovative prospective for the prevention and treatment of CKD.Citation170

Distinctive characteristics of the gut microbiota in CKD patients, when compared to healthy controls, have been elucidated through research, revealing an increased abundance of Proteobacteriaceae and Enterobacteriaceae, along with a decreased abundance of Fecal bacilli, Rosebacterium, Clostridium IV, Eubacterium, Bifidobacteriaceae, Lactobacillus, and Ruminococcaceae170. Among them, Proteobacteriaceae indicates metabolic disruption of the patients, which is commonly associated with higher risks of HTN, ASCVD and HF. Notably, Lactobacillus and Veillonellaceae exhibited a positive correlation with the estimated glomerular filtration rate (eGFR), a parameter indicating CKD severity, while Enterobacteriaceae displayed a negative correlation with eGFR.Citation170 These findings underscore the vital role played by the gut microbiota in the initiation and progression of CKD.

In CKD mice, indole sulfate, primarily synthesized by intestinal E. coli through tryptophan metabolism, elicits mitochondrial autophagy damage and intestinal barrier dysfunction by upregulating interferon regulatory factor 1 (IRF1), thereby aggravating renal burden.Citation171 CKD patients exhibit elevated plasma levels of TMAO, which have been linked to prognosis. Notably, additional experiments using animal models have demonstrated that TMAO can activate the TGF-β/Smad3 signaling pathway by phosphorylating Smad3, culminating in kidney fibrosis and collagen deposition.Citation172 Another noteworthy functional trait of the gut microbiota in CKD patients is the diminished presence of bacteria responsible for SCFA production. This reduction in SCFAs contributes to CKD progression by impairing the intestinal barrier and provoking inflammatory responses.Citation173

In recent years, a growing body of in vivo and in vitro studies has provided compelling evidence that the administration of probiotics holds promise in reducing uremic toxin levels, mitigating circulating inflammatory mediators, and preserving the integrity of the intestinal barrier in individuals with uremia. A clinical study found that oral administration of synbiotics which consisted of a combination of high – molecular weight inulin, fructo-oligosaccharides, galacto-oligosaccharides, Lactobacillus, Bifidobacteria, and Streptococcus genera can reduce serum levels of uremic toxins in CKD patients.Citation174 Further research is needed on their specific mechanism. Supplement of Faecalibacterium prausnitzii to CKD mice attenuated renal dysfunction and its associated CVDs risks via its metabolite butyrate and downstream renal GPR43.Citation103 These beneficial effects of probiotics serve to enhance the overall quality of life for patients afflicted by this condition.Citation173

Coronary artery disease and gut microbiota

Coronary artery disease (CAD) continues to dominate as the primary cause of adult mortality globally and represents a significant contributor to morbidity and mortality among the elderly population.Citation175 Recent investigations have firmly established a causal association between the gut microbiota and CAD, thereby highlighting the gut microbiota as a potential target for both the prevention and treatment of CAD.Citation176

Studies have revealed notable alterations in the gut microbiota of CAD patients, including a significant increase in the Firmicutes to Bacteroidaceae ratio and abundance of Lactobacillus, along with a significant decrease in the abundance of Bacteroidaceae, encompassing Bifidobacteriaceae and Prevotella176. Additionally, Jie et al. identified distinctive features in the gut microbiota of ASCVD patients, characterized by a decreased abundance of Bacteroidaceae and Prevotella, alongside a significant increase in the abundance of Enterobacteriaceae and Streptococcus177.

The gut microbiota-derived metabolite TMAO has emerged as a recognized risk factor for CAD, as substantiated by multiple studies.Citation23,Citation176,Citation177 Notably, TMAO plays a pivotal role in promoting foam cell formation, a crucial pathological manifestation in the progression of ASCVD, by upregulating the expression of macrophage CD36, scavenger receptors (SRs), and heat shock proteins.Citation178,Citation179 Furthermore, TMAO exerts a sensitizing effect on platelet reactivity through the inositol trisphosphate (IP3) pathway, thereby fostering platelet aggregation and contributing to the progression of ASCVD.Citation180 Investigations have unveiled a negative correlation between the production of butyrate by Roseburia intestinalis and CAD development in murine models. Subsequent studies have demonstrated that butyrate ameliorates circulating inflammatory cytokine levels and retards CAD progression by inhibiting nuclear NF-κB and modulating local Treg cells.Citation68 Phenylacetylglutamine (PAG), a gut microbiota-dependent metabolite influenced by Bacteroidaceae, Firmicutes, and Proteobacteria, heightens platelet sensitivity and the risk of blood clot formation, thereby elevating the risk of CAD.Citation181,Citation182 Another tryptophan metabolite produced by gut microbiota, indole-3-carboxaldehyde (ICA), derived from Bacteroidaceae and Lactobacillus, exerts a protective effect in CAD by modulating the AhR pathway and reducing circulating levels of reactive oxygen species (ROS).Citation183

Significant strides have been achieved in elucidating the role of the gut microbiota in the treatment of CAD. Notably, inhibiting the gut microbiota-dependent production of TMAO has emerged as a promising therapeutic strategy for combating atherosclerosis.Citation184 Administration of Lactobacillus rhamnosus GG to CAD patients has demonstrated the ability to reduce endotoxemia and confer positive effects on CAD.Citation185 Furthermore, Lactobacillus plantarum 299 v supplementation has been shown to improve endothelial function and ameliorate systemic inflammation in male individuals with CAD.Citation186 Both Lactobacillus rhamnosus GG and Lactobacillus plantarum 299 v improved CAD by increasing the generation of SCFAs in the intestine and improving endothelial inflammation of blood vessels. Clinical investigations have revealed that supplementation with the probiotic Bifidobacterium lactis Probio-M8 in CAD patients leads to decreased serum inflammatory cytokine levels and blood lipid levels, thereby improving CAD development.Citation187 Another study employed oligosaccharide supplementation in CAD patients, resulting in an increased abundance of Faecalibacterium, Alistipes, and Escherichia in the gut, while the abundance of Bacteroides, Megasphaera, Roseburia, Prevotella, and Bifidobacterium decreased. Following treatment, the patients exhibited reduced blood lipid levels and improved cardiac function.Citation188 Therefore, targeting the gut microbiome holds a pivotal role in the prevention and treatment of CAD.

Atrial fibrillation and gut microbiota

AF stands as the prevailing form of rapid cardiac arrhythmia, with its prevalence escalating in tandem with advancing age. Among individuals aged 80 and above, approximately 10%-12% are affected by AF.Citation189 The principal therapeutic modalities for atrial fibrillation encompass pharmacological control and radiofrequency ablation. Nevertheless, our comprehension of AF’s etiology remains incomplete, necessitating further investigation to devise preventive and management strategies.

In recent years, a burgeoning body of research has unveiled the potentially pivotal role of gut microbiota in the onset and progression of AF. Investigations have unveiled an augmented abundance of Ruminococcaceae, Streptococcus, and Enterococcus, accompanied by a reduced abundance of Fecal bacilli, Alistipes, Oscillibacter, and Bilophila within the gut microbiota of AF patients.Citation190 Remarkably, AF could be “transmitted” through the transplantation of fecal microbiota from aged AF-susceptible rats to young rats, thereby implicating the involvement of the gut microbiota in AF pathogenesis.Citation191,Citation192

The activation of the NLRP3 inflammasome has emerged as a contributing factor to atrial fibrosis and heightened susceptibility to AF.Citation191 Study have elucidated that reduced levels of SCFAs in dysregulated gut microbiota can mitigate NLRP3 inflammasome activation via the GPR43/NLRP3 signaling pathway, consequently decelerating AF progression. The susceptibility of mice to AF under burst pacing was found in low fiber diet mice model, while the susceptibility to AF decreased after SCFAs supplementation.Citation193 Conversely, elevated levels of LPS in gut microbiota metabolites bolster NLRP3 inflammasome activity, thereby fostering AF progression.Citation191,Citation193,Citation194 Increased plasma levels of TMAO intensify the infiltration of M1 macrophages in the atria, culminating in atrial remodeling and potentially serving as a novel mechanistic underpinning of AF.Citation195 Collectively, these findings underscore the significant role of the gut microbiome in the occurrence and progression of AF, highlighting the modulation of gut microbiota as a promising new target for the prevention and treatment of AF.

Heart failure and gut microbiota

HF represents a growing public health crisis characterized by chronic impairment of cardiac function stemming from diverse etiologies. Its prevalence surpasses 10% in individuals aged 70–84 and exceeds 30% in those aged 85 and above, exerting a substantial toll on the health of the elderly population.Citation196 Gut microbiota assumes a pivotal role in the occurrence and progression of HF. Recent investigations have unveiled that TMAO fosters HF by activating the Smad3 signaling pathway,Citation197 triggering the NF-κB signaling pathway,Citation149 and modulating myocardial fatty acid oxidation.Citation198 These mechanisms contribute to cardiac hypertrophy and fibrosis, with circulating TMAO levels serving as prognostic markers for HF.Citation199 The “gut-HF hypothesis” posits that reduced cardiac output and circulatory congestion in HF patients lead to intestinal ischemia, edema, and subsequent gut dysbiosis. This dysbiosis induces endotoxemia and elevated plasma inflammatory factors, thereby exacerbating HF progression. SCFAs, vital energy sources for intestinal epithelial cells, play a critical role in maintaining gut homeostasis and intestinal barrier function, consequently mitigating this detrimental cycle and exerting a favorable impact on HF.Citation150 Furthermore, SCFAs can modulate the RAS and serve as energy substrates for failing myocardium, contributing to the amelioration of HF progression.Citation200 Investigations have unveiled an association between circulating PAG levels and HF severity, with PAG promoting HF development.Citation201 Moreover, PAG can serve as a prognostic indicator for HF patients.Citation202,Citation203 Propionic acid ImP, a metabolite of Eggerthella lenta and Streptococcus mutans, has recently been linked to congestive HF severity. Physiological research has suggested that ImP can disrupt mitochondrial membrane potential, thereby implicating its potential role in perturbing cardiac myocyte function.Citation204

Can probiotic supplementation prevent the occurrence and progression of HF? A double-blind trial discovered that supplementation with Saccharomyces boulardii resulted in enhanced cardiac function and reduced uric acid levels in HF patients.Citation205 However, subsequent clinical trials demonstrated that after three months of treatment with either Saccharomyces boulardii or the non-absorbable antibiotic rifaximin, no significant improvement in cardiac function was observed.Citation206 Another study unveiled that administration of Lactobacillus rhamnosus to rats with coronary artery occlusion preserved left ventricular function, suggesting a potential beneficial role of Lactobacillus rhamnosus in ameliorating HF.Citation207 High-fiber diets have been shown to stimulate the production of gut microbial metabolites, such as acetate, which could protect intestinal barrier and mitigate HF risk in hypertensive mice.Citation138 The gut microbiota emerges as a promising target for HF therapy, although research still remains limited. Further experimental investigations are warranted to identify specific probiotics that can enhance the prognosis of HF patients and explore the potential benefits of FMT in HF treatment.

Future perspectives

The past 10 years of microbiome research provides intriguing, though still controversial, evidence of the relationships between microbes and different CVDs and the nuances of these mechanism. They provide significant help and strengthen our hope to use gut microbiota for prevention, diagnosis, treatment and recovery. However, a substantial literature gap still separates experimental observations and clinical application targeted at gut microbiota in CVDs.

Efforts should be directed toward establishing more robust connections between gut microbes and CVDs. Previous investigations have predominantly focused on elucidating alterations in gut microbial composition within specific CVDs, identifying functional metabolites, and exploring their potential molecular mechanisms (). However, to progress beyond mere correlation and establish causality, it is crucial to provide more direct evidence and linkages. Specifically, it is essential to investigate the specific gut microbiota species or strains that are characteristic of particular diseases and ascertain their capacity to produce bioactive substances that elicit distinct cardiac phenotypes. FMT to germ-free mice, to some extent, help to explain this causality. Nonetheless, the quality and result of this experiment are influenced by a various of factors, nearly involving every step throughout its procedure from feces collection and storage to post-transplantation treatment.Citation212 And there still exits controversy regarding to certain experiment condition. A constantly updated and unified guideline should be developed, which would largely promote the accuracy, consistency and reproducibility.

Table 1. Characteristics of gut bacteria in CVDs of different life stages.

Research would also be worthwhile heading toward novel mechanisms. In the domain of CVDs, a diverse array of mediators plays a pivotal role in facilitating communication between gut microbiota and target organs. While considerable research efforts have predominantly focused on elucidating the contributions of bacterial metabolites and structural products in CVDs, the exploration of alternative mediators remains relatively limited. However, the metabolites profiles vary largely among populations and are greatly influenced by diet, metabolism, digestion, etc. The discrepancies between gut microbiota taxonomic composition by metagenomics and blood metabolites profiles by metabolomics should also arouse our concern when exploring metabolite-based mechanisms.Citation213 The inter-kingdom atlas involving bacterial-fungi and bacterial-virus interplay is also intriguing and is largely unknown in CVDs. The recent identification of microbial-host isozyme provides novel and promising perspective for developing CVD therapeutical target.Citation214 A comprehensive exploration of the underlying mechanisms that drive CVDs is warranted, as it holds the potential to unlock novel insights and foster the development of more precise therapeutic interventions.

Future research would make unremitting endeavors toward accurate CVDs diagnosis. Through the integration of the aforementioned mechanisms, the possibility of developing novel diagnostic strategies for CVDs emerges, contingent upon the individualization and minimally invasive nature of gut microbiota detection methods. However, the diagnosis and predictive system based on gut microbiota should take individual characters into consideration, including genetic background, strain, sex, antibiotic use etc. Machine learning (ML) and artificial intelligence (AI) techniques offer considerable promise in this domain, enabling the creation of improved diagnostic panels that can accurately assess the risk of specific CVDs based on gut microbiota composition. Remarkable progress has already been made, as successful ML frameworks have been established, linking gut microbiota with T2DM and facilitating risk prediction.Citation215 In addition, Aryal et al. demonstrated the potential of ML by utilizing five ML algorithms to predict CVD risk based on gut microbiota composition, exemplifying the role of ML in noninvasive diagnostics.Citation216 Future research endeavors should prioritize the establishment of ML frameworks encompassing diverse CVD types and their correlation with gut microbiota. Such comprehensive investigations will contribute to disease prediction, phenotypic classification, and the development of personalized profiles for patients.

Identification of disease-specific or individual-specific alterations in gut microbiota paves the way for the development of individualized treatments targeting diverse diseases and populations. The prevention and treatment methods modulating gut microbiota includes but not limits to probiotics, prebiotics, diet therapy and lifestyle correction(). Identifying new strategies to assemble and administer commensal bacterial consortia help to reconstruct and optimize the altered gut microbiome in CVDs.Citation225 Improving fermentation procedures and developing CVDs benefit fermented foods and beverages also hold great promise in prevention.Citation226 The insights derived from gut microbiota research can be harnessed to design tailored therapeutic strategies that cater to the unique requirements of patients afflicted with CVDs.

Table 2. Gut microbiota modulation in CVDs of different life stages.

Conclusions

The gut microbiota develops, matures and ages together with the host, interacting with and participating in the occurrence and development of CVDs. There are significant and specific changes in the gut microbiota of CVDs patients or animal models, through which noninvasive diagnostic strategies can be developed with the aid of newly emerging artificial intelligence and machine learning. These systems could also be applied to predict the classification, staging, and prognosis of different CVDs. Based on the research foundation of the interactions between the gut microbiota and CVDs, targeted interventions targeting the gut microbiome, such as direct administration of specific bacteria, dietary changes, and administration of gut microbiota metabolites, have achieved promising results and held great translational promise (). Analyzing the gut microbiome of patients with different CVDs throughout lifelong stages and providing targeted precise treatment will be the ultimate goal of future research.

Figure 2. Opportunity of targeting gut microbiota to affect lifelong CVDs care.

Diagnosis of host CVDs could be achieved by detecting the characteristic alteration in specific gut microbes, blood gut microbiota metabolites, bacterial nucleic acids, and bacterial structural products. Multi-omics studies linking heat, blood and gut together reveal the correlations and bioinformatic analysis with machine learning help to predict prognosis. By targeting intestinal microbiome, from birth mode, feeding mode, living habits, biological agents and other intervention methods, great opportunity emerges in preventing the progress of risk factors and treating CVDs.
Figure 2. Opportunity of targeting gut microbiota to affect lifelong CVDs care.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All relevant data are within the paper.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (grant number 82172101, 82072081), the Natural Foundation of Shanghai Science and Technology Committee (grant number 23Y11907000, 23ZR1440900), Shanghai Jude Charitable Foundation.

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