Recent research has made significant progress in elucidating the mechanisms by which oral bacteria translocate to the gut. A study published in Gut Microbes in 2024 demonstrated that oral pathobiont Klebsiella spp. can specifically adhere to inflamed intestinal mucosa via chaperone-usher pili (CUP), a surface protein structure (Guo et al., 2024). During conditions such as inflammatory bowel disease or after antibiotic treatment, the intestinal epithelial barrier becomes more permeable, allowing oral bacteria swallowed during normal digestion to cross the compromised barrier and colonize the gut lumen. Once established, these oral bacteria can disrupt the gut microbial balance, leading to a reduction in beneficial short-chain fatty acid (SCFA)-producing bacteria and an increase in pro-inflammatory cytokines. This imbalance may promote the translocation of bacterial lipopolysaccharides (LPS) into the bloodstream, triggering systemic inflammatory responses (Apoorva, 2020; Guo et al., 2024).

There may be a metabolic cross-feeding relationship between the oral and gut microbiota. Although direct evidence is currently lacking to confirm a significant positive correlation between salivary lactate produced by oral lactic acid bacteria and fecal short-chain fatty acids (SCFAs) synthesized by gut bacteria, existing studies have shown that lactic acid bacteria can influence the composition and metabolic activity of the gut microbiota (Li et al., 2024). Lactic acid bacteria ferment dietary carbohydrates into lactate, which can be further metabolized by certain gut bacteria—such as Veillonella and Bacteroides—into acetate and propionate. Propionate has been demonstrated to modulate host energy metabolism and inflammation by activating G protein-coupled receptors (e.g., GPR41 and GPR43) on immune cells, thereby inhibiting the NF-κB signaling pathway and reducing the production of pro-inflammatory cytokines (Akhtar et al., 2022). In addition, propionate can stimulate the secretion of glucagon-like peptide-1 (GLP-1) from intestinal endocrine cells, contributing to improved glucose homeostasis and potentially protecting cardiovascular health by reducing insulin resistance (Kimura et al., 2011).

Notably, recent research has begun to reveal the unique role of gut fungi in the metabolism-inflammation axis. Cross-kingdom interactions between fungi and bacteria also show potential synergistic pathogenic mechanisms. For instance, when Candida albicans and Streptococcus mutans coexist in dental plaque biofilms, they enhance biofilm structural stability and pro-inflammatory capacity (Falsetta et al., 2014; Ellepola et al., 2019). This “fungus-bacterium interaction” mechanism has recently been proposed as a potential new driver of inflammatory diseases, including cardiovascular conditions. Therefore, exploring the metabolic cross-feeding and inflammatory synergy between fungi and bacteria within oral and gut ecosystems may provide new insights into the pathogenesis of systemic metabolic diseases.

In the early stages of the disease, oral pathogens such as Porphyromonas gingivalis and Fusobacterium nucleatum may be swallowed through the oropharynx and enter the gut, where they disrupt the balance of the gut microbiota. For instance, colonization by F. nucleatum has been associated with a reduction in Lactobacillus populations (Xie et al., 2024), accompanied by decreased levels of anti-inflammatory cytokines (e.g., IL-10) (Zhao et al., 2019) and increased levels of pro-inflammatory cytokines (e.g., IL-17, TNF-α) (Chen et al., 2015; Gebremariam et al., 2019). IL-17 can activate vascular endothelial cells and upregulate the expression of VCAM-1 and ICAM-1, thereby promoting immune cell adhesion and migration to the vessel wall, creating a pro-inflammatory environment conducive to plaque formation (Mai et al., 2016). Notably, recent studies have provided direct evidence of oral pathogens in atherosclerotic tissue. In 2017, J-L C Mougeot and colleagues used 16S rRNA gene-based metagenomic analysis to identify 230 species of oral microbiota within atherosclerotic plaques, with P. gingivalis being the most abundant (Mougeot et al., 2017). This supports a potential causal relationship between oral infections, atherosclerosis, and cardiovascular events.

The oral–gut microbiota axis also plays a crucial role in cholesterol metabolism. Trimethylamine-N-oxide (TMAO), a metabolite produced by gut bacteria from dietary choline and carnitine, has been closely linked to atherosclerosis. Studies have shown that TMAO can inhibit the expression of cholesterol transporters ABCA1 and ABCG1 in macrophages, reducing cholesterol efflux and leading to intracellular cholesterol accumulation and foam cell formation—a hallmark of atherosclerotic plaques (Luo et al., 2024). Additionally, TMAO can activate the TLR4/NF-κB signaling pathway, thereby promoting inflammatory responses and accelerating atherosclerosis progression (Hakhamaneshi et al., 2021). Interestingly, oral bacteria such as Prevotella and Fusobacterium are also capable of producing TMA, suggesting that the oral microbiome may indirectly contribute to atherosclerosis by influencing TMAO production (Nakajima et al., 2015).

In the later stages of atherosclerosis, the oral–gut microbiota axis may contribute to plaque instability and thrombosis through systemic inflammation and metabolic disruption. Chronic periodontitis can lead to oral pathogens such as P. gingivalis, or its virulence factors (e.g., lipopolysaccharide [LPS] and gingipains), being swallowed into the gut, where they disrupt the microbial ecology. Studies have shown that such dysbiosis increases pro-inflammatory bacteria like Enterobacteriaceae and Fusobacterium, while decreasing barrier-protective and butyrate-producing bacteria. This induces increased intestinal permeability (“leaky gut”), allowing pathogen-associated molecular patterns such as LPS to more easily enter the circulation, triggering systemic inflammation (Nakajima et al., 2015; Sun et al., 2024). This systemic inflammation can activate matrix metalloproteinases (MMPs) within atherosclerotic plaques, leading to degradation of collagen and elastin, thereby weakening plaque structure (Di Nubila et al., 2024). In addition, circulating oral-derived toxins (e.g., P. gingivalis LPS) can activate endothelial cells and platelets via the TLR4/NF-κB signaling pathway, promoting platelet adhesion, aggregation, and inflammation. In recent years, P. gingivalis DNA has also been detected in coronary thrombi of patients with acute myocardial infarction (Piñon-Esteban et al., 2020; Joshi et al., 2022), and its secreted gingipains can activate protease-activated receptors (PAR-1 and PAR-4) on platelets, inducing aggregation and pro-inflammatory cytokine release (Khalaf et al., 2017). Its lipopolysaccharides may also activate immune cells through the TLR4/NF-κB pathway (Khalaf et al., 2017). These dual mechanisms may promote thrombosis and exacerbate atherosclerosis. Therefore, the oral–gut microbiota axis not only contributes to systemic inflammation through local infections but also disrupts gut barrier function and microbiota composition, promoting a pro-inflammatory vascular environment and platelet activation, potentially serving as a critical driver of plaque rupture and acute cardiovascular events.

Oral microbiota dysbiosis may lead to alterations in gut microbial composition, subsequently affecting the integrity of the intestinal barrier (Murugesan and Al Khodor, 2023). When this barrier is compromised, lipopolysaccharide (LPS) from the outer membrane of Gram-negative bacteria can enter systemic circulation, resulting in endotoxemia. LPS activates the Toll-like receptor 4 (TLR4) signaling pathway, inducing the production of proinflammatory cytokines and reactive oxygen species (ROS) in vascular endothelial and smooth muscle cells. The increase in ROS impairs endothelial nitric oxide synthase (eNOS) function, reducing nitric oxide (NO) production, a key vasodilator. The subsequent vasoconstriction and increase in peripheral vascular resistance ultimately lead to elevated blood pressure (Dinakis et al., 2024).

The oral-gut axis can also activate the renin-angiotensin system. Gut microbiota-derived short-chain fatty acids (SCFAs), such as propionate and butyrate, modulate the RAS via G protein-coupled receptors (e.g., GPR41, GPR43, and Olfr78). For instance, propionate activates GPR41 to promote vasodilation and lower blood pressure, whereas Olfr78 activation may increase renin release and raise blood pressure. SCFAs also regulate renal gene expression of renin and angiotensinogen, thereby affecting RAS activity (Pluznick et al., 2013; Gotoh and Shibata, 2023). Furthermore, systemic inflammation caused by oral and gut dysbiosis can stimulate the release of angiotensin-converting enzyme (ACE) (Nobbs et al., 2009; Ge et al., 2013), leading to RAS activation, sodium and water retention, increased blood volume, and eventually elevated blood pressure (Schenkein and Loos, 2013; Santisteban et al., 2017).

Notably, in the past five years, the role of the gut-brain axis in hypertension—particularly resistant hypertension—has gained increasing attention. Metabolites produced by gut microbiota, such as SCFAs, can influence the central nervous system via the vagus nerve, regulating sympathetic nervous activity and thereby affecting blood pressure. In addition, gut dysbiosis may increase proinflammatory cytokines such as IL-17 and TNF-α, which can activate central nervous system inflammation and further promote the development of hypertension (Cui et al., 2024).

A 2024 review published in the International Journal of Molecular Sciences highlights that dysbiosis of the oral microbiota is closely associated with the development of cardiovascular diseases (CVD) (Mai et al., 2016). Oral pathogens and their metabolites can enter the bloodstream either directly through the oral mucosa or indirectly by translocating to the gut, thereby triggering systemic inflammatory responses. In patients with heart failure, such inflammation may further impair cardiac function. For example, the presence of pathogenic bacteria such as Porphyromonas gingivalis is associated with elevated levels of high-sensitivity C-reactive protein (hs-CRP) and other pro-inflammatory cytokines, which may contribute to myocardial fibrosis, reduced cardiac contractility, and decreased cardiac output.

A 2023 study published in the American Journal of Physiology – Heart and Circulatory Physiology observed compositional shifts in the gut microbiota of heart failure patients, characterized by a reduction in beneficial bacteria and an increase in pathogenic ones (Ahmad et al., 2023). The study also reported a decline in short-chain fatty acids (SCFAs) such as butyrate, which may be associated with disease progression. However, in some cases, these microbiota changes may represent an adaptive response aimed at maintaining host metabolic and immune homeostasis in the context of heart failure.

Notably, certain bacterial genera exhibit “double-edged sword” effects in heart failure. For instance, Akkermansia muciniphila is widely recognized for its metabolic benefits: it strengthens the intestinal mucus layer, modulates immune responses, and produces anti-inflammatory metabolites such as SCFAs, which can improve metabolic profiles and endothelial function (Everard et al., 2013). However, under pathological conditions such as compromised intestinal barriers or inflammation, A. muciniphila’s mucin-degrading activity may increase gut permeability, facilitate the translocation of pathogens like Salmonella, and trigger systemic inflammation, potentially exacerbating cardiovascular damage (Hikima et al., 2021).

In light of these findings, the “strain-specific function hypothesis” has been proposed: different strains of the same microbial species may exert markedly different, even opposing, physiological effects. For example, A. muciniphila strains vary significantly in membrane protein expression, immune modulation capacity, and metabolite production. Some strains may induce protective immune responses, while others could be pathogenic (Zhang and Zhao, 2016). Therefore, future microbiota-based therapies should shift from a species-level to a strain-level precision design, in order to enhance therapeutic efficacy and avoid potential risks.

Bacteriophages are viruses that specifically infect and lyse certain bacteria and have been increasingly studied as a targeted antimicrobial therapy alternative to antibiotics. In studies on the oral-gut axis, phages have been designed to eliminate oral pathogens that promote cardiovascular diseases (CVD), such as Fusobacterium nucleatum (Kowalski et al., 2022) and Porphyromonas gingivalis (Brodala et al., 2005; Matrishin et al., 2023).

Research has found that P. gingivalis harbors prophages, suggesting that its ecological system may be regulated by phages (Matrishin et al., 2024). A 2019 study discussed the CRISPR-Cas system in P. gingivalis, focusing on how it protects against phage infection through adaptive immune mechanisms within periodontal pockets (Chen and Olsen, 2019). A 2023 study analyzed the CRISPR-Cas systems of “red complex” bacteria associated with periodontitis (including P. gingivalis) and found that these systems may help bacteria resist phage infection by identifying and neutralizing phage DNA (Yadalam et al., 2023). Therefore, engineering phages using CRISPR-Cas systems to enhance their specificity and effectiveness against P. gingivalis is becoming a cutting-edge direction in precision microbial intervention research.

Since phages can kill bacteria within minutes, phage therapy may lead to endotoxin release rapidly and cause adverse reaction including hypersensitivity and cytokine release syndromes (Liu et al., 2021). An case report in German Heart Center Berlin showing 3 of 4 patients with cardiovascular implant infections were infection free after bacteriophage therapy, indicated phage therapy could be applied as an alternative strategy for patients with chronic relapsing cardiovascular implant infections (Tkhilaishvili et al., 2022). No adverse events related to phage application were reported in the first safety trial in England about bioavailability of oral phage in humans (Bruttin and Brüssow, 2005). Besides, a retrospective observational study including 100 cases of bacteriophage therapy in Belgium reported that more that 70% patients with clinical improvement but there were 15 adverse events including seven non-serious adverse drug reactions suspected to be linked to bacteriophage therapy (Pirnay et al., 2024). Further clinical trials are needed to assess the safety of phage therapy application.

In recent years, combined intervention strategies have also emerged. In the 2019 review article Phage Therapy: A Renewed Approach to Combat Bacterial Infections published in Cell Host & Microbe, Kortright et al. highlighted the mechanistic differences between phages and traditional antibiotics and proposed that their combination might yield synergistic effects (Kortright et al., 2019). They also suggested that prebiotics and probiotics could enhance the efficacy of phage therapy by modulating the host microbiota. Although this review was largely theoretical, it provided direction for future studies and emphasized the potential of combination therapies in antimicrobial treatment. A 2022 study demonstrated that combining phages with the probiotic Lactobacillus reuteri significantly alleviated colitis symptoms caused by Salmonella in a mouse model and promoted short-chain fatty acid (SCFA) production, suggesting the potential of combined strategies in modulating the microbiota (Wang et al., 2022). In 2024, a study found that in a mouse model of colitis, the use of fructooligosaccharides (FOS), Saccharomyces boulardii, and their combination yielded more significant anti-inflammatory effects and improved modulation of the gut microbiota (Wu et al., 2024a).

Additionally, host genetics also significantly influence the microbiome. For example, polymorphisms in the FMO3 gene affect the metabolism of TMAO, suggesting the potential for personalized microbial interventions based on genetic profiling (Moradzad et al., 2022).

Metabolites serve as key mediators in the crosstalk between the oral-gut axis and cardiovascular disease. Among them, trimethylamine N-oxide (TMAO), a metabolite produced by the gut microbiota through the metabolism of dietary choline and L-carnitine, has been shown to promote atherosclerosis (Zhu et al., 2020). Currently, researchers are developing inhibitors targeting key enzymes involved in TMAO production. For example, 3-nitrooxypropanol (3-NOP) inhibits FMO3, thereby blocking the conversion of TMA to TMAO. Early studies have demonstrated its significant TMAO-suppressing effects. Meanwhile, several small-molecule compounds have been developed to target choline-TMA lyase, reducing TMA production by up to 60% in vitro (Bollenbach et al., 2020). Another direction focuses on promoting the synthesis of beneficial metabolites, particularly SCFAs such as butyrate and propionate. Studies have shown that the intake of prebiotics such as inulin can enhance the abundance of Bifidobacteria and Lactobacilli, thereby boosting SCFA levels and reducing inflammation (van der Beek et al., 2018). In a clinical study, a 12-week high-inulin diet intervention significantly increased SCFA levels and improved systemic inflammation and blood pressure in patients with metabolic syndrome (Neyrinck et al., 2021).

Furthermore, postbiotics are being explored as a novel therapy, involving the direct use of microbial metabolic products such as purified butyrate or bacterial cell wall components to exert anti-inflammatory effects and protect vascular endothelium. For instance, a 2023 study found that butyrate, by activating GPR43 receptors, reduced atherosclerotic plaque formation (Ma et al., 2023).