Coronary heart disease (CHD) is a condition in which the arteries cannot supply adequate oxygenated blood to the heart. Most cases of CHD are caused by the blockage of coronary arteries due to either atherosclerosis, thrombosis, or a combination of both (Ulbricht and Southgate, 1991).

The effects of gut microbiota in CHD are due to alterations in their composition and metabolites. One previous study enrolling 29 CHD inpatients and 35 healthy volunteers showed the proportion of phylum Bacteroidetes (56.12%) was lower, whereas that of the phylum Firmicutes was higher (37.06%) in the CHD patients than that of the healthy controls (60.92% and 32.06%, P <0.05) (Cui et al., 2017). Elsewhere, a similar observation was obtained (Emoto et al., 2017). Furthermore, a case-control study revealed that lower Lactobacillus levels are associated with an increased likelihood of severe coronary atherosclerotic lesions and myocardial necrosis as well as a poorer prognosis for patients with the acute coronary syndrome (ACS), particularly those with ST-segment elevation myocardial infarction (Gao et al., 2021). A previous study showed that Faecalibacterium was the dominant microorganism in the healthy control group, whereas Escherichia-Shigella and Enterococcus were enriched in the coronary artery disease group (Zhu et al., 2018). Furthermore, Yang et al. showed that hydroxyurea effectively treated atherosclerosis, reduced serum cholesterol levels, modified the gut microbiota at various levels, and affected cholesterol absorption by decreasing Niemann-Pick C1-like 1 in the epithelial cells of small intestines of apolipoprotein E knockout ApoE^(-/-) mice fed on a high-fat diet (Yang et al., 2022b). In addition, the severity of myocardial infarction in rats is associated with intestinal microbial metabolites (Lam et al., 2016). The gut microbiome can also affect lipid metabolism. Certain bacteria in the gut microbiome can metabolize BAs, thereby affecting lipid metabolism. On the other hand, dysbiosis can alter the production of BAs, causing changes in lipid metabolism and increasing the risk of atherosclerosis (Jonsson and Bäckhed, 2017). The gut microbiome can affect the development and progression of atherosclerosis and CHD in various ways. Firstly, inflammatory responses can exacerbate plaque development or cause plaque rupture. Secondly, cholesterol and lipids metabolism by the gut microbiota can influence the development of atherosclerotic plaques. Thirdly, diet and gut microbial metabolites, including TMAO and SCFAs, can have various effects on atherosclerosis (Jonsson and Bäckhed, 2017; Liu et al., 2020a).

Hypertension is one of the most prevalent risk factors for CVDs across the globe. Furthermore, hypertension arises due to a complex interplay of genetic and environmental factors (Li et al., 2021a; Zhou et al., 2021). Globally, hypertension and pre-hypertension account for 8.5 million deaths annually due to stroke, ischemic heart disease, other vascular disorders, and kidney diseases. The prevalence of hypertension among individuals aged 30-79 years doubled from 648 million people to 1278 million people between 1990 and 2019 (Zhou et al., 2021).

Unlike healthy controls, patients with hypertension show microbial diversity and a shift in microbial composition. In addition, the number of species associated with hypertension shows a stronger correlation with disease severity. Li et al. found that pre-hypertensive and hypertensive patients had significantly reduced microbial richness and diversity. They also exhibited distinct metagenomic composition characterized by an overgrowth of disease-associated bacteria and a decrease in healthy-associated bacteria. Additionally, these patients exhibited a Prevotella-dominated gut enterotype and disease-linked microbial function, in contrast to the healthy control group (Li et al., 2017). Surprisingly, the microbiome characteristics of the pre-hypertensive group were similar to those observed in the hypertensive group. In addition, a previous study enrolling 60 patients with primary hypertension and 60 gender-, age-, and body-weight-matched healthy controls revealed that opportunistic pathogenic bacteria such as Klebsiella spp., Streptococcus spp., and Parabacteroides merdae were frequently found in the gut microbiome of hypertensive individuals. In contrast, beneficial bacteria producing SCFAs, such as Roseburia spp. and Faecalibacterium prausnitzii, were more abundant in the control group. Short-chain fatty acids-producing bacteria can modulate blood pressure by promoting vasodilation. In terms of microbial function, the gut microbiome of hypertensive individuals exhibited higher membrane transport, lipopolysaccharide (LPS) biosynthesis, and steroid degradation. However, the healthy controls showed higher metabolism of amino acids, cofactors, and vitamins (Yan et al., 2017). Furthermore, dysbiosis of the gut microbiome in rat models of hypertension can directly influence systolic blood pressure. Therefore, modulation of the gut microbiota can be exploited as a novel therapeutic approach for managing hypertension (Durgan et al., 2016; Adnan et al., 2017). Australian researchers recently published a review article, summarizing the latest research findings on the role of gut microbiota and their metabolic byproducts in host blood pressure regulation mechanisms. Gut microbiota imbalances can affect blood pressure regulation via host gene pathways, vascular function, and the autonomic nervous system. Enteric bacterial metabolites, including SCFAs and indole-3-lactic acid, are beneficial, whereas TMAO is harmful to blood pressure. Regulating gut microbiota through diet or fecal microbiota transplantation (FMT) may serve as a potential therapeutic strategy for blood pressure reduction. Moreover, the article discussed the prospects, challenges, and difficulties of using gut bacteria for blood pressure control in clinical applications (O’Donnell et al., 2023).

Heart failure is a complex clinical syndrome characterized by dyspnea and fatigue due to its inability to efficiently fill or eject blood from the heart. Heart failure can progress to pulmonary or splanchnic congestion and peripheral edema. It can be categorized into four types, including heart failure with preserved ejection fraction (HFpEF), heart failure with mildly reduced ejection fraction (HFmrEF), heart failure with reduced ejection fraction (HFrEF), and heart failure with improved ejection fraction (HFimpEF). HF is a leading cause of morbidity and mortality across the globe. The 2022 guideline offers patient-centric recommendations for healthcare professionals to prevent, diagnose, and manage patients with heart failure (Heidenreich et al., 2022).

Alteration of gut microbiota composition and microbial metabolite shifts, especially those derived from dietary nutrients increase the risk of HF. Tang et al. reported that impaired intestinal barrier function and bowel wall edema in HF patients might promote local and systemic inflammation, as well as bacterial translocation (Tang et al., 2019b). In addition, the inflammation and immune response linked to intestinal barrier impairment and bacterial translocation can exacerbate heart failure (Jia et al., 2019). Moreover, Zhang et al. showed that TMAO was involved in the pathological processes of HF and could act as a marker for identifying patients at risk of disease progression. In addition, they reviewed the gut–TMAO–HF axis as a new target for HF treatment (Zhang et al., 2021b). Romano et al. investigated the relationship between the gut microbiota-derived metabolite phenylacetylgutamine (PAGln) and HF. Clinical and mechanistic analyses reveal a dose-dependent association between circulating PAGln levels and HF presence and severity. PAGln directly promotes HF-relevant phenotypes, including decreased cardiomyocyte sarcomere contraction and elevated B-type natriuretic peptide gene expression in both cultured cardiomyoblasts and murine atrial tissue. The findings suggest that regulating the gut microbiome, particularly PAGln production, may represent a potential therapeutic target for modulating HF (Romano et al., 2023). This together suggests that innovative therapeutic approaches that target gut microbial metabolic pathways or metabolites and modify the gut microbiota composition could be effective in reducing CVDs susceptibility and preventing the progression of HF.

In recent years, numerous studies have investigated gut microbiota as a therapeutic target for CVDs prevention and management. For example, a previous study demonstrated that Bacteroides fragilis could prevent aging-related atrial fibrillation (AF) in rats through regulatory T cells (Tregs) mediated regulation of inflammation. Specifically, Bacteroides fragilis promotes the proliferation and function of Tregs as well as reduces inflammatory responses, thus decreasing the incidence of AF (Zhang et al., 2022). These findings provide novel insights for developing new drugs to prevent or treat AF. Furthermore, a clinical study showed that SCFAs could alleviate the development of AF through G protein-coupled receptor 43/NOD-like receptor family pyrin domain containing 3 (GPR43/NLRP3) signal pathways (Zuo et al., 2022). Moreover, the potential of probiotics, prebiotics, and FMT in modulating gut microbial composition and promoting cardiovascular health has been extensively studied (Oniszczuk et al., 2021). However, further studies are needed to reveal microbial mechanisms with diagnostic and therapeutic implications in CVDs (Walker et al., 2021). Furthermore, a previous study showed that hydroxyurea could prevent diabetic cardiomyopathy by inhibiting inflammation and cell apoptosis (Zhou and Lu, 2022). Inflammation is implicated in CVDs. In addition, dysbiosis has been linked to increased inflammation. A few gut microbiota, particularly Gram-negative bacteria, produce LPS, which activate the immune system and promote inflammatory responses (Yoo et al., 2020).

In summary, the gut-heart axis represents a complex network of interactions involving the gut microbiota, their metabolites, and the cardiovascular system. Myocarditis, an important cardiovascular disease, has gained significant attention in recent years. The emergence of the gut-heart axis concept might imply a potential connection between the gut microbiota and myocarditis. By delving into the role of the gut microbiota in myocarditis, we may discover new opportunities for prevention, diagnosis, and treatment, ultimately enhancing the prognosis and quality of life for those affected.

Gut microbiota is involved in the regulation of host immunity. For example, Lactobacilli and Bifidobacteria improve the host immune function (Vlasova et al., 2016). Furthermore, the gut microbiota stimulate the training and development of the host immune system and the occurrence of cellular immunity, enabling the host’s innate immune system to distinguish between pathogenic and symbiotic bacteria (Wu and Wu, 2012; Ursell et al., 2014; Yoo et al., 2020). In addition, the gut microbiota colonizes, and proliferates in the intestinal mucosa, forming a layer that protects the host from invasion by foreign pathogens. In addition, gut microbiota can compete with harmful bacteria for nutrients, thereby inhibiting their growth and generating antibacterial substances that suppress the proliferation of pathogens (Belkaid et al., 2014).

Gut microbiota primarily affects the disease process through endogenous metabolites produced by gut microbiota and changes in the composition of gut microbiota. About 70~80% of the human immune cells are found in the gut, and dysbiosis of the gut microbiota is related to alterations in the immune system. Emerging evidence has focused on the role of the gut microbiota in regulating the immune response to viral infections and has shown that the gut microbiota can influence the activity of immune cells, including T cells and dendritic cells (Mizutani et al., 2022). Specifically, some gut microbiota produces metabolites that modulate the activity of immune cells and the production of pro-inflammatory cytokines, thus promoting the development of myocardial inflammation. Figure 3 shows the possible relationship between gut microbiota and their metabolites, immune system, and myocarditis.

Gut bacteria can be classified into six primary phyla based on their genetic and physiological characteristics, including Firmicutes, Bacteroides, Actinobacteria, Proteobacteria, Fusobacteria, Verrucomicrobia, and some other phyla. Firmicutes, Bacteroides, Actinobacteria, and Proteobacteria, account for over 90% of the gut microbiota (Yan et al., 2022). (1) The phylum Firmicutes includes several common gut bacteria, such as Lactobacillus, Streptococcus, and Clostridium. Some Firmicutes species improve gut barrier function and enhance immunity (Rinninella et al., 2019). (2) The phylum Bacteroidetes include several bacteria that produce SCFAs, such as Bacteroides fragilis. Short-chain fatty acids have anti-inflammatory effects on the gut and promote immune homeostasis (Fabersani et al., 2021). (3) The phylum Proteobacteria includes several pathogenic bacteria, including Escherichia coli and Salmonella, which can cause gastrointestinal infections. However, some Proteobacteria, such as Akkermansia muciniphila, have beneficial effects on gut health, including promoting the growth of beneficial bacteria and reducing inflammation (Larsen et al., 2015). (4) The phylum Actinobacteria includes numerous beneficial gut bacteria, such as Bifidobacterium and Collinsella, which modulate the immune system, improve gut barrier function, and reduce inflammation (Barka et al., 2016).

Gut microbiota-dependent metabolites act as a bridge that connects the dynamic equilibrium between the host and the gut microbiota (Schoeler et al., 2019). The gut microbiota generates numerous small-molecule metabolites during microbial food digestion, playing a vital role in communication between host cells and gut bacteria (Ursell et al., 2014). The metabolites could have beneficial or harmful effects. Over the past decade, more than 300 endogenous metabolites of gut bacteria, including SCFAs, BAs, monoamines, biogenic amines, indole derivatives, phenols, vitamins, branched-chain amino acids (BCAAs), and lipids, have been discovered through non-targeted and targeted metabolomic analyses. Among them, extensive studies have been conducted on the primary endogenous metabolites, including, SCFAs, BAs, BCAAs, and TMAO (monoamines). These metabolites play significant roles in various physiopathologic processes. Furthermore, lipopolysaccharides, produced by Gram-negative bacteria, have also attracted attention for their effect on the host through metabolism-independent signaling pathways(Yang et al., 2021). This highlights the importance of understanding the complex interactions between these metabolites and their potential roles in human health and disease (Li et al., 2018b; Wang et al., 2018).Therefore, this section presents the effect of gut microbial metabolites on the host from the perspective of the immune system.

Viral myocarditis is a significant cause of heart failure and dilated cardiomyopathy. Viral infection of the myocardium can lead to myocardial cell necrosis. The pathological and physiological mechanisms of viral myocarditis have been investigated using murine models of enterovirus infection, especially coxsackievirus B3 (CVB3) (Lin et al., 2021). The CVB3 cardiomyophilic strain virus (CVB3m) and the CVB3 non-cardiomyophilic strain virus (CVB3o) are variants of the CVB3 standard strain, which can be adapted for different research objectives to achieve the required pathology of myocarditis in specific tissue types (Błyszczuk, 2019).

Viral entry into the myocardium results in three kinds of responses. The acute phase is characterized by viral entry and replication, the subacute phase is characterized by inflammatory cell infiltration, and the chronic phase is characterized by cardiac remodeling. Myocardial injury includes direct injury mediated by viral infections and indirect injury due to secondary immune responses (Henke et al., 1995). The molecular mechanisms underlying injury were described in detail in a review published in 2016. Targeting these virus-encoded proteases may inhibit viral replication and viral direct damage to the myocardium (Fung et al., 2016). The adaptive immune responses begin after the acute and subacute phases of myocarditis (Lin et al., 2021). Opavsky et al. established gene knockout mice CD4^(-/-), CD8^(-/-), both co-receptors (CD4^(-/-) CD8^(-/-)), or T cells receptor beta chain (TCR beta ^(-/-)) to investigate the impact of T cell subsets on host susceptibility to CVB3 myocarditis. They found that myocarditis severity in the CD4 knockout group, CD4 and CD8 knockout group, and TCR beta knockout group was lighter than that in the CD8 knockout group. Moreover, IFN-γ levels were elevated while TNF-αlevels were suppressed in CD4 and CD8 knockout mice models (Opavsky et al., 1999). Chemokines are a class of small cytokines or signaling proteins secreted by cells. They can induce nearby responsive cells to directionally migrate towards the source of chemokines. A transgenic study involving mice models revealed that CXC chemokine ligand 10 (CXCL10) was upregulated in the early stages of myocardium infection and inhibited viral replication in the early CVB3 infection stages by recruiting NK cells and promoting IFN-γ expressions. However, in the late infection stages, it did not stimulate the antiviral effects to improve the survival rates of mice (Yuan et al., 2009). Male mice with CVB3-induced myocarditis had myocardial infiltrating macrophages expressing increased markers, including inducible nitric oxide synthase, IL-12, TNF-α, and CD16/32, which are associated with classically activated macrophages (M1) (Li et al., 2009).

Mice models are important in studies on autoimmune diseases (Lincez et al., 2011). Experimental autoimmune myocarditis mice models distinguish between autoimmune phases of viral myocarditis from the acute infection phase of CVB in genetically modified mice (Blyszczuk et al., 2008). Disease severity is classified based on the infiltration extent of inflammatory cells during the peak of inflammation. This model can also be used for other types of myocarditis (Błyszczuk, 2019).

Neu et al. reported that autoimmune myocarditis is often indirectly associated with a viral infection. One possible contributing factor is the release or exposure of cardiac myosin after viral-mediated myocyte damage, which induces autoimmune responses and myocardial inflammation (Neu et al., 1987). Pdcd1^-/-Ctla4^+/- mice spontaneously develop fulminant myocarditis. Therefore, Axelrod et al. performed single-cell sequencing and single-cell TCR sequencing of immune cells infiltrating these myocarditis tissues and found that CD8⁺ T cells were significantly increased in number and showed clonal expansions. Myocarditis did not develop when CD8⁺ T cells were removed from these mice. When CD4⁺ T cells were the only ones to be removed, myocarditis incidences did not change. When CD8⁺ T cells from Pdcd1^-/-Ctla4^+/- mice were adoptively transferred to Rag1^-/- mice, the recipient mice developed myocarditis after two months. Therefore, CD8⁺ T cells are highly involved in fulminant myocarditis development (Axelrod et al., 2022). A recent study also found that macrophage migration is a significant histopathological feature of myocarditis, indicating that macrophages are potential therapeutic targets for this disease (Toita et al., 2021).

FMT, a natural microbial ecosystem in feces, involves the transfer of fecal material from a healthy donor to a recipient to restore a healthy gut microbiota composition and functions (Wang et al., 2019a). Infant colonization by a specific microbial community, largely originating from the mother, is a natural process that rapidly occurs after birth and is influenced by the delivery mode (Fuentes and de Vos, 2016). As early as the 4^th century BC, Chinese medical books recorded the use of fecal preparations to treat gastrointestinal diseases (Wargo, 2020). FMT can effectively treat recurrent Clostridioides difficile infections, and there is a growing interest in the use of FMT in other diseases, including inflammatory bowel disease and metabolic syndromes (Davidovics et al., 2019). The success rate of FMT relies on the composition of the recipient’s microbiome and the interplay between the microbiomes of the donor and recipient at both taxonomic and functional levels (Kazemian et al., 2020). FMT can provide a diverse range of microbial communities which play an important role in restoring functional redundancy of gut microbiota. However, there exist limitations in terms of reproducibility, whereas factors including safety, donor/recipient considerations, dosing, and administration route should be taken into account when considering FMT. Studies on the use of FMT, specifically in the context of myocarditis, are limited (Hu et al., 2019). Further, the safety and efficacy of FMT in myocarditis treatment should be investigated.

1) The LBPs are a type of therapeutic agent comprising many live microorganisms, typically bacteria, ingested or applied to the body for disease prevention and treatment (Charbonneau et al., 2020). They are also referred to as “live biotherapeutics” or “live biotherapeutic agents” (Dhansekaran and Sankaranarayanan, 2021). They differ from probiotics or prebiotics in that they are specifically designed to deliver a therapeutic effect (Dreher-Lesnick et al., 2017; Charbonneau et al., 2020). They are produced under strict manufacturing processes to ensure the viability and efficacy of bacteria when administered to the patient. Some clinical trials are assessing the efficacy of this strategy of regulating gut microbiota in cancer immunotherapy (Wargo, 2020). The potential of LBPs to treat various conditions, including gastrointestinal, metabolic, and immune system disorders is being investigated. A previous review outlined the factors to be considered during the design and development of genetically engineered LBPs to ensure compliance with regulatory standards and gain acceptance from patients (Charbonneau et al., 2020).

2) Antibiotics are drugs that can kill or inhibit the growth of bacteria. Excess or improper use of antibiotics can lead to gut microbiota dysbiosis (Gough, 2022). Probiotic supplementation is a treatment approach that can promote gut microbiota recovery. Probiotics are live microorganisms such as Bifidobacterium, Saccharomyces, Lactic acid bacteria, Lactobacillus acidophilus, Actinomycetes, and Lactobacillus rhamnosus with health benefits upon consumption (Hill et al., 2014). Probiotic supplementation reduces myocardial hypertrophy and heart failure following myocardial infarction in rat models (Gan et al., 2014). Intestinal stem cell regeneration was accelerated by Lactobacillus rhamnosus GG, which promoted colonic barrier recovery in septic mice (Chen et al., 2023). In vitro, anti-inflammatory activities of probiotic supernatants are unique, since they can modulate interleukin 1β (IL-1β), IL-6, TNF-α, and IL-10 production in human macrophages in distinct approaches (De Marco et al., 2018). Probiotic supplementation is considered safe for individuals with functional immune systems (Vallianou et al., 2020). Still, they may induce immune responses, require cold storage, and cannot be used with antibiotics (Suez et al., 2019).

3) Symbiotics are combinations of probiotics and prebiotics with synergistic effects on gut microbiota composition and function. They are developed to address the potential challenges associated with probiotics survival in the gastrointestinal tract (Rioux et al., 2005). Consumption of yogurt and fruits may have combined health benefits due to their potential prebiotic and probiotic effects (Fernandez and Marette, 2017).

1) Prebiotics are nondigestible food ingredients that selectively stimulate the growth and activities of beneficial gut microbiota. They primarily consist of bifidogenic, non-digestible oligosaccharides, such as inulin, its hydrolysis product oligofructose, and (trans) galactooligosaccharides (de Vrese and Schrezenmeir, 2008). Prebiotics include nutritional supplements that promote gut microbiota proliferation. The natural sources of prebiotics include beans, cereals, and soybean among others (Kerry et al., 2018). They may reduce inflammatory responses and improve cardiac functions by regulating gut microbiota. Similar to findings from studies involving adult studies, prebiotic effects in infant nutrition results in significant alterations in gut microbiota composition, with a notable increase in Bifidobacteria levels in fecal matter (Roberfroid et al., 2010).

2) Postbiotics, gaining attention as health-promoting agents, are beneficial compounds produced through the metabolic activities of microorganisms, particularly probiotics. These diverse substances, including cell wall components, SCFAs, and enzymes, have various effects on the host, such as modulating the immune system, improving gut barrier function, and inhibiting pathogenic bacteria growth (Żółkiewicz et al., 2020); Tsilingiri and Rescigno, 2013). As a stable and safe alternative or complement to traditional probiotics, postbiotics show promise in maintaining and improving human health, necessitating additional research to optimize their production and develop effective therapies.

3) Food plays a vital role in shaping gut microbiota composition and diversity. Dietary interventions, including the Mediterranean diet and Dietary Approaches to Stop Hypertension diet, have beneficial effects on gut microbiota composition and cardiovascular health (Merra et al., 2020; Drapkina et al., 2022). The Mediterranean diet, rich in fruits, vegetables, whole grains, legumes, fish, and olive oil, improves gut microbiota composition, reduces frailty and improves health status (Ghosh et al., 2020). The Dietary Approaches to Stop Hypertension (DASH) diet, rich in fruits, vegetables, whole grains, and low-fat dairy products, reduces blood pressure and improves cardiovascular health (Maifeld et al., 2021). A Western-style diet, rich in saturated fats, salt, and sugar, reduces gut microbiota diversity which increases the prevalence of inflammatory disease (Statovci et al., 2017). Plant-based diets, rich in fibers, are associated with increased gut microbiota diversity and reduced cardiovascular disease risks (Satija and Hu, 2018; Losno et al., 2021).

1) The gut microbiome plays a crucial role in mediating host-environment interactions and exhibits a complex bidirectional relationship with non-antibiotic drugs. This intricate interplay involves the microbiome influencing drug efficacy and toxicity, while simultaneously being affected by the drugs themselves, a phenomenon known as pharmacomicrobiomics (Weersma et al., 2020). We review the relevant research on the interactions between gut microbiota and cardiovascular medications. Silva et al. discovered that statin therapy is a key covariate affecting gut microbiome diversity by analyzing the data from 888 volunteers in the Body Mass Index Spectrum cohort from the MetaCardis project. In patients with ACS under statin medications, the potentially pathogenic bacteria in the gut are reduced, with a better prognosis. Analysis of fecal samples suggests that the gut microbial communities of obese individuals taking cholesterol-lowering statin medications are “healthier” than expected, suggesting that the potential beneficial effects of statins on gut microbiota open up new prospects for disease treatment (Vieira-Silva et al., 2020). Yang et al. discovered a previously unrecognized mechanism in which the human commensal bacteria, Coprococcus comes, catabolizes ester ACE inhibitors in the gut, reducing their antihypertensive effects. The findings revealed that gut microbiota may play a role in the efficacy of antihypertensive medications, which could help explain why some individuals remain resistant to treatment (Yang et al., 2022a). Another study found that liraglutide could treat patients with type 2 diabetes mellitus by targeting the gut microbiota (Shang et al., 2021)

In clinical practice, traditional Chinese medicine (TCM) is orally administered and bidirectionally interacts with the gut microbiota. These interactions have two primary effects: (1) Enhancing effects: TCM modulates gut microbiota composition and metabolism, improving host health while the microbiota enhances TCM bioavailability. (2) Inhibitory effects: Some TCM constituents can weaken gut microbiota metabolic functions, and certain microbes may inhibit TCM absorption and metabolism (Zhu et al., 2023). A recent review revealed that numerous natural molecules (e.g., apigenin, berberine, and quercetin) and plant extracts can effectively alleviate experimental autoimmune myocarditis. Key anti-myocarditis mechanisms include the upregulation of Th1-type cytokines, the elevation of Th2-type cytokines (IL-4 and IL-10), mitigation of oxidative stress, modulation of mitogen-activated protein kinase signaling pathways, and increased sarco-endoplasmic reticulum Ca2⁺-ATPase levels (Javadi and Sahebkar, 2017). These molecules and extracts can alter the composition and abundance of gut microbiota, suggesting that they hold great potential as treatments that target gut microbiota.

The use of antibiotics can not only fight against pathogenic bacteria, but also affect the intestinal symbiotic flora. Compared to other antibiotics, the gut symbiotic bacteria are more sensitive to macrolides and tetracyclines. Some detoxifying agents protect the gut symbiotic bacteria from antibiotic damage (Maier et al., 2021). Haak et al. found that a one-week course of combined broad-spectrum antibiotics (ciprofloxacin, vancomycin, and metronidazole) has a profound and long-lasting impact on the gut microbiota of healthy humans, causing loss of diversity and shifts in community composition. Although the microbiota showed a remarkable return towards baseline after 8-31 months, the community composition often remained altered, with the long-term consequences remaining largely unknown (Haak et al., 2019).

2) Moreover, Mamic et al. summed up the application of gut microbiome in heart failure and its comorbidities. They highlighted that targeting gut microbial enzymes, which are not found in the host, is a promising approach to overcoming these challenges. The study focuses on the TMAO meta-organismal pathway and suggests that 3,3-dimethy-1-lbutanol, a natural inhibitor of TMA lyases, may be a non-lethal and elegant strategy to target this pathway. In mice fed a high choline diet, administration of 3,3-dimethy-1-lbutanol resulted in decreased circulating TMAO levels, decreased foam cell formation, and fewer atherosclerotic plaques. Targeted inhibition of microbial choline-TMAO conversion was also evaluated in a pressure overload mice model of heart failure, where it improved cardiac remodeling and cardiac function. The study proposes that both pharmacologic modification of the TMAO biosynthetic pathway and targeted dietary interventions may be viable strategies for modulating the pathogenesis and progression of heart failure. However, further human studies are necessary to evaluate the feasibility and efficacy of this approach (Mamic et al., 2021).

Gut microbiota dysbiosis is implicated in the pathogenesis of many diseases. The LBPs, FMT, pre/probiotics, postbiotics, synbiotics, and dietary interventions have the potential for disease prevention or treatment by modulating gut microbiota. The future of promoting overall health and treating diseases by regulating intestinal microorganisms is becoming clearer, and more strategies and methods to regulate gut microbiota are known (Wargo, 2020). The various approaches have shown promising results in animal studies, however, their effectiveness and safety for myocarditis treatment should be investigated further. Elucidating the mechanisms by which gut microbiota contribute to myocarditis pathogenesis may lead to the development of novel therapeutic approaches targeting the gut microbiota.

The current treatment options for myocarditis are limited, and there is a need for new approaches to improve outcomes. Targeted gut microbiome therapy is a promising approach; however, it is still in the early developmental stages, and more research is necessary to determine its efficacy and safety. Several challenges and limitations to the development of gut microbiota-targeted therapies are defined by alternatives, such as FMT, and LBPs, as well as by the lack of a clear mechanistic understanding of disease pathophysiology. Another challenge is the lack of knowledge about the roles of specific bacteria in myocarditis pathogenesis (Mandelbaum et al., 2020). Although studies have reported that certain bacteria may be involved in the development of this condition, it is still unclear which bacteria are most important and how they interact with the host immune system (Hu et al., 2019). This limits the capacity to develop targeted therapies that can effectively treat myocarditis.

One of the challenges of targeted gut microbiome therapy is the need for personalized treatment. The gut microbiome is highly individualized, and bacterial composition can vary widely from person to person, therefore, a one-size-fits-all approach to treatment is unlikely to be effective. Instead, personalized treatment plans that take into account the specific bacteria present in each patient’s gut microbiome are needed (Wargo, 2020). Precision medicine approaches, such as genomics, metabolomics, and various omics techniques can help in identifying specific bacterial strains that are associated with myocarditis and develop personalized treatment plans based on these findings (Caesar et al., 2021).

Despite the challenges of targeted gut microbiome therapy, it holds great promise in myocarditis treatment. One direction for future research is to identify new targets for therapy based on better understanding of interactions between the gut microbiome and the host immune system. Studies should aim at investigating the etiology, pathogenesis, and gender differences of myocarditis (Tschöpe et al., 2021).

Moreover, it’s possible to apply machine learning and artificial intelligence to analyze gut microbiome data, which can enhance our understanding of the connection between the gut microbiome and myocarditis. By adopting this innovative approach, we can identify previously unknown therapeutic targets and create more personalized treatment plans for individual patients (Loganathan and Priya Doss, 2022).

There is a need for personalized treatment plans based on specific bacteria present in each patient’s gut microbiome (Behrouzi et al., 2019). Targeted gut microbiome therapy has the potential to revolutionize myocarditis treatment and improve disease outcomes. There is a need for large-scale animal and clinical trials to evaluate the safety and efficacy of targeted gut microbiome therapy in myocarditis treatment. Moreover, studies should also explore the optimal timing and duration of treatment and assess the long-term effects of this therapy on patient outcomes.