Coronary heart disease (CHD) is the leading cause of death worldwide. The 2010 Global Burden of Disease Study predicted that its incidence will increase by 50% by 2030 compared with 2010 (Lozano et al., 2012). The lifetime risk of coronary heart disease for people over 40 is approximately 49% for men and 32% for women (Mathers and Loncar, 2006). Dyslipidemia, blood glucose, blood pressure, and obesity are recognized risk factors for coronary heart disease, and dietary patterns play a key role in regulating disease risk and progression (Lloyd-Jones et al., 2002). As a well-validated statistical method, descending regression (RRR) has been widely used to explore the association between dietary patterns and coronary heart disease-related outcomes. Carotid intima-media thickness (CCA-IMT) serves as a reliable early indicator of atherosclerosis progression (Kromhout et al., 2002). A multicenter observational study found that a baseline RRR dietary pattern characterized by high intake of refined grains, processed red meat, and sugar-sweetened beverages (typical features of WD) was significantly and positively associated with CCA-IMT (Ding et al., 2025). Studies in Western regions have further confirmed that the group mainly composed of WD has a higher CCA-IMT value and the incidence of carotid artery stenosis (Nettleton et al., 2007). With the process of globalization, the WD model has also affected the Asian population: multiple studies in the Middle East have found that an increase in the intake of fat, red meat and carbohydrates, while a decrease in the intake of fruits, vegetables and green leafy vegetables, is positively correlated with the risk of coronary artery disease (Oikonomou et al., 2018). Excessive sugar intake in the diet, as a typical feature of the WD pattern, is an independent risk factor for the development of coronary heart disease (Schwab et al., 2014). A randomized controlled trial demonstrated that high sugar intake directly increases cardiovascular risk by raising blood pressure and low-density lipoprotein cholesterol (LDL-C) levels —these key factors exacerbate the risk of coronary heart disease (Fung et al., 2009). Epidemiological studies have also found that high intake of red meat and processed meat is associated with elevated serum cholesterol, which is a recognized predictor of coronary heart disease (Te Morenga et al., 2014). As early as 1908, Ignatowski observed that rabbits fed a diet high in cholesterol and saturated fat would develop atherosclerotic lesions, which proved that saturated fatty acids and cholesterol could increase serum cholesterol concentration (Steffen et al., 2005). In addition, low-density lipoprotein receptor-deficient male mice fed a low-fat diet showed significant lipid accumulation and increased mortality (McGill, 1979). Processed meat products in low-fat diets are rich in sodium, nitrates and preservatives, which can produce potential carcinogenic compounds (such as heterocyclic amines and polycyclic aromatic hydrocarbons) during cooking. These substances are epidemiologically associated with an increased risk of coronary heart disease (Bogen and Keating, 2001; Lakshmi et al., 2005; Meydani et al., 2014).

Breakthroughs in high-throughput sequencing technology have significantly deepened our understanding of gut microbiota dysregulation in the pathogenesis of congenital heart disease (CHD). A rigorously controlled clinical study involving 29 CHD patients and 35 healthy controls found significant microbial community alterations in CHD patients with decreased abundance of Bacteroidetes and Proteobacteria, and increased levels of Firmicutes and Fusobacteria (Zhu et al., 2016). Subsequent metagenomic analysis results were highly consistent with this finding (Dinakaran et al., 2014). It is worth noting that the proportion of Firmicutes and Bacteroides in CHD patients is increased, which is significantly positively correlated with metabolic disorders such as obesity and dyslipidemia. Mechanism studies have shown that this imbalance of microbiota promotes ectopic fat deposition by enhancing energy acquisition efficiency and improving intestinal nutrient absorption (Gostimirovic et al., 2023). FMT experiments in animal models have provided experimental evidence for the direct causal relationship between the composition of intestinal microbiota and the progression of CHD. Studies have confirmed that susceptibility to atherosclerosis can be transmitted horizontally through the gut microbiota (Zhu et al., 2016). Furthermore, clinical studies have found that compared with the healthy control group, the relative abundance of Bacteroides and Bifidobacterium in patients with coronary heart disease is significantly reduced, and this reduction is negatively correlated with the level of fecal lipopolysaccharide (LPS) (Manco, Putinani, and Botazzo), which is consistent with the phenomenon of elevated fecal LPS concentration in patients with coronary heart disease reported in early epidemiological data in Japan (Dinakaran et al., 2014; Cui et al., 2017).

The metabolic products of intestinal microorganisms, as bioactive signaling molecules, can regulate the progression of coronary heart disease. LPS, also known as endotoxin, is mainly located on the outer membrane of Gram-negative bacteria. As a potent systemic inflammation inducer, it has been recognized as a biomarker for coronary heart disease (Yoshida et al., 2018). Changes in the intestinal flora will increase the permeability of the intestinal barrier, allowing LPS to enter the circulatory system. This influx of LPS reduces high-density lipoprotein (HDL) levels, impedes cholesterol transport and promotes cholesterol deposition in the vessel wall—further increasing the risk of coronary heart disease (Saad et al., 2016). TMAO as another key microbial metabolite, has always been associated with the incidence of coronary heart disease. Multiple studies have confirmed that the concentration of circulating TMAO is positively correlated with the risk of coronary heart disease (Ding et al., 2025). TMAO is synthesized in the liver by intestinal microbiota metabolizing dietary precursors (such as phosphatidylcholine, choline, carnitine) (Cui et al., 2017). Excessive intake of choline and carnitine (commonly found in WD) leads to elevated TMAO levels, which promotes the transformation of macrophages into cholesterol-enriched foam cells, thereby accelerating the progression of atherosclerosis (Vakadaris et al., 2025). SCFAs, including acetic acid, propionic acid and butyric acid, are key mediators in the pathogenesis of coronary heart disease. The abundance of butyric acid-producing bacteria (e.g., Roseobacter intestinalis and Faecalis prausnii) is significantly reduced in patients with CHD, suggesting that gut microbiota may influence the development of CHD by modulating SCFA lineage (Tang et al., 2013). SCFAs have cardioprotective effects: for instance, dietary supplementation with 1% butyrate can reduce inflammation and delay the progression of atherosclerosis by enhancing plaque stability (Blacher et al., 2017); Propionate prevents cardiac hypertrophy, fibrosis and hypertension through T-cell-dependent mechanisms (Aguilar et al., 2014). Acetate and propionate can adjust vasomotor function and blood pressure levels, reduce systemic inflammatory response and atherosclerotic lesions, and at the same time as an independent predictor of high blood pressure—this is a significant risk factor for coronary heart disease (Bartolomaeus et al., 2019).

HF is the end-stage manifestation of a variety of CVD and remains a major clinical challenge in cardiovascular care. In the late stage of the disease, HF causes low pumping efficiency or reduced output of the heart due to left ventricular dysfunction, resulting in insufficient cardiac output (unable to meet metabolic demand) and multi-organ congestion with volume overload (Oikonomou et al., 2018). A very low-calorie diet significantly exacerbates heart damage caused by transverse aortic coarctation (Steinbusch et al., 2011). A high-fat and high-sugar diet not only leads to weight gain in WD-fed mice, but also triggers unique cardiac features, including cardiac insufficiency and metabolic dysfunction (Chen et al., 2017). After 16 weeks of WD exposure, mice developed diastolic dysfunction (Gallet et al., 2016), and similar cardiac diastolic function and individual cardiomyocyte function impairment were also observed in Osaba pigs fed with WD (Nguyen et al., 2017). Approximately half of HF cases belong to HF with preserved ejection fraction (HFpEF), which is characterized by impaired diastolic function (Olver et al., 2019). The triglyceride content in the hearts of mice fed WD increased (Steinbusch et al., 2011). Long-term intake of WD can impair glucose tolerance and disrupt cardiolipin metabolism, ultimately leading to systemic metabolic dysfunction of cardiomyocytes (Vileigas et al., 2021; Ballal et al., 2010). Wd-induced obesity, dyslipidemia, and systemic insulin resistance increase the risk of HF (Ballal et al., 2010). Mechanistically, excessive intake of sugar and fat forces the heart to increase glucose uptake and overactivate insulin signaling pathways, leading to the accumulation of toxic lipid intermediates (e.g., triglycerides, ceramide) in cardiomyocytes (Procópio Pinheiro et al., 2020). Studies on transgenic mice have also shown that an increase in fatty acid uptake and storage in cardiac tissue leads to triglyceride and neuramide deposition, which is closely related to histopathological changes and impaired diastolic function (Shiojima et al., 2002; Finck et al., 2002). Fatty acids regulate cardiometabolic function and mitochondrial function by activating peroxisome proliferator-activated receptors (PPARs). However, a long-term high-fat diet (the core component of WD) can lead to excessive fatty acid oxidation (FAO), which in turn causes elevated serum TG, cardiac insulin resistance, left ventricular hypertrophy (LVH), and diastolic dysfunction (Finck et al., 2002; Yagyu et al., 2003; Burkart et al., 2007). There is contradictory evidence regarding the role of omega-3 polyunsaturated fatty acids (PUFAs) in HF: Male Wistar rats supplemented with omega-3 PUFAs can reduce stress overload induced LVH, improve diastolic dysfunction and alleviate cardiac insufficiency in the short term, but HF progression still occurs eventually (Brigadeau et al., 2007; Duda et al., 2009). This highlights the complexity of the effects of WD on HF -given its typically high omega-6 and low omega-3 PUFA content -while its role in HF risk remains controversial.

The abundance of opportunistic pathogens (including Campylobacter, Shigella, Salmonella, Yersinia, and Candida) was significantly increased in HF patients (Trøseid et al., 2015). Subsequent clinical cohort studies further confirmed that the alpha diversity of the gut microbiota in HF patients was negatively correlated with the severity of cardiac dysfunction, accompanied by elevated levels of systemic inflammatory response and oxidative stress (Pasini et al., 2003). 16S rRNA sequencing was used to analyze the gut microbiota of 20 patients with reduced ejection fraction type HF (caused by ischemic or dilated cardiomyopathy), and it was found that the internal classification diversity of HF patients was significantly reduced—manifested as a decrease in the relative abundance of Coryneaceae, Erythemataceae, and Ruminococcus (Wang et al., 2022). This discovery further confirms the association between intestinal flora imbalance and the pathogenesis of HF. The decline in microbial diversity and the enrichment of pathogenic bacteria may accelerate the progression of the disease.

Patients with HF usually present with reduced cardiac output and peripheral circulation congestion, which in turn leads to intestinal ischemia and edema, resulting in impaired intestinal barrier function (Zhang, 2025). This barrier dysfunction promotes the entry of harmful metabolites (such as LPS) into the systemic circulation, generating pro-inflammatory stimulation, damaging myocardial function and accelerating the deterioration of HF. Metabolomics studies have revealed that the pathogenesis of HF is closely related to bile acid metabolism disorders (Maggioni et al., 2010). Therapeutic regimens that modulate bile acid metabolism, particularly ursodeoxycholic acid supplementation, have been shown to improve peripheral circulation and prevent reperfusion injury in patients with HF. Experimental studies have further confirmed that bile acids exhibit cardioprotective effects in animal models by enhancing myocardial contractility and improving hemodynamic parameters (Qu et al., 2023). As a key mediator in the pathophysiology of HF, the mechanism of TMAO has also attracted much attention. Clinical studies have shown that elevated TMAO levels are associated with left ventricular diastolic dysfunction and poor prognosis, and persistently high TMAO concentrations are positively correlated with HF mortality (Suzuki et al., 2019; Purcell et al., 2001). The triggering effect of TMAO on HF may involve multiple mechanisms, including promoting myocardial fibrosis, damaging endothelial function, and intensifying systemic inflammation—these factors collectively lead to cardiac remodeling and a decline in cardiac function. SCFAs also play an important role in the progression of HF. The number of bacteria that produce SCFAs in patients with HF (such as Faecobacter propani and Rosaceae genus) decreases, leading to a reduction in SCFA levels (Pasini et al., 2003). SCFAs typically have the functions of regulating the integrity of the intestinal barrier, reducing inflammatory responses and regulating blood pressure—the absence of these protective functions may further aggravate HF. For instance, butyrate enhances the intestinal epithelial barrier function by promoting the expression of tight junction proteins, while acetate and propionate alleviate systemic inflammation by inhibiting the production of pro-inflammatory cytokines such as TNF-α and IL-6. Therefore, the decreased level of the calcitonin gene (SCFA) in patients with HF may form a vicious cycle of intestinal barrier dysfunction, inflammatory response and cardiac damage.

Myocardial infarction (MI) is a disease caused by the accumulation of plaques in the inner membrane of arteries, which leads to blocked blood supply to the heart and hypoxia, resulting in myocardial damage. MI, as a leading cause of death worldwide, has over 140,000 cases in the United States alone each year (Cilla et al., 2016; Smit et al., 2020). Dietary habits are closely related to the risk of myocardial infarction: especially the intake of red meat increases iron load, leading to adverse cardiometabolic consequences (Poursafar et al., 2019). Epidemiological studies have shown that high red meat intake in Costa Rica is an important risk factor for myocardial infarction (Lloyd-Jones et al., 2002), and a case-control study in Iran also found a significant positive correlation between red meat intake and the risk of myocardial infarction (Lu et al., 2015). High-fat diets (HFDs, a major component of WD) exacerbate cardiovascular complications in animal models: in aged rats, a high-fat diet significantly worsens hypertensive heart disease, leading to worsening atrial and ventricular remodeling and impaired left ventricular systolic function (Albrektsen et al., 2023). High-fat diets also trigger multiple post-MI complications, including myocardial fibrosis, endothelial dysfunction, and impaired ventricular function (Salari et al., 2023). In the mouse model, the levels of arachidonic acid (AA) and thromboxane B2 (TXB2) in mice fed a HFD diet were significantly higher than those in the control group (Watanabe et al., 2012). Arachidonic acid (AA), as one of the most abundant polyunsaturated fatty acids, can trigger inflammatory reactions, and its downstream metabolite TXB2 is significantly increased in the acute phase of myocardial infarction. These findings suggest that a high-fat diet may exacerbate the inflammatory response after myocardial infarction (Zhao et al., 2020). In addition, a low-fat diet can further aggravate cardiac remodeling after myocardial infarction by inducing cardiac hypertrophy, myocardial cell apoptosis, and interstitial fibrosis, ultimately leading to heart failure (Velagaleti et al., 2008; Santos et al., 2017). Conversely, a beneficial dietary pattern can provide cardiovascular protection. A diet rich in fish, fruits, vegetables, and polyunsaturated fats was associated with a 23% reduced risk of myocardial infarction.

Recent studies have revealed a significant association between gut microbiota composition and myocardial infarction (MI). In patients with acute myocardial infarction (AMI), the abundance of Firmicutes decreased, the abundance of Bacteroidetes slightly increased, and the bacterial genera such as Macrococcus, Butyromonas, acidophilus, and desulfurvibrio significantly increased (Shariff et al., 2017). Animal experiments confirmed reduced microbial diversity and changes in the relative abundance of key taxa in the MI model (Cui et al., 2017). Bacterial invasion and translocation play a key role in the development of MI. The levels of LPS and bacterial ribosomal DNA (rDNA) in the circulatory system of MI patients are elevated, which may affect the cardiac inflammatory response and prognosis after MI (Manco et al., 2010; Tang et al., 2019; Zhou et al., 2018). Serum LPS levels were significantly higher in patients with MI than in controls, and LPS concentrations were positively correlated with blood bacterial load—suggesting that increased intestinal permeability after MI may lead to intestinal bacteria entering the circulation (Carnevale et al., 2020). In addition, serum LPS levels are strongly correlated with the neutrophil/lymphocyte ratio (NLR), white blood cell count, and neutrophil count—these systemic inflammatory markers (Carnevale et al., 2020). The germ-free mouse experiment further verified the role of the gut microbiota in MI. The deficiency of intestinal flora significantly reduced the levels of serum LPS and inflammatory cytokines. This leads to a reduction in cardiac inflammation and an improved prognosis of myocardial infarction (MI), indicating that the translocation of gut microbiota metabolites is a new mechanism for excessive inflammation and severe myocardial injury in MI patients (Carnevale et al., 2020).

Lps-mediated myocardial infarction is a key microbial metabolite driving the pathogenesis of myocardial infarction. After myocardial infarction, due to the reduction in cardiac output and intestinal ischemia leading to intestinal barrier dysfunction, LPS can enter the systemic circulation. LPS activates the Toll-like receptor 4 (TLR4) signaling pathway in immune cells and cardiomyocytes, triggering the release of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β. These cytokines can exacerbate myocardial inflammation, promote myocardial cell apoptosis and impede myocardial repair, thereby deteriorating the prognosis of myocardial infarction (Han et al., 2021; Carnevale et al., 2020). A high-fat diet is also involved in the progression of myocardial infarction. Intestinal flora imbalance caused by high-fat diet and excessive intake of choline/carnitine can lead to high levels of TMAO, thereby enhancing platelet hyperreactivity: in animal thrombosis models, TMAO promotes thrombosis by accelerating platelet activation (Wang et al., 2011). TMAO will increase the risk of coronary artery thrombosis—a major cause of MI. In addition, a high-fat diet promotes the instability of atherosclerotic plaques by increasing macrophage infiltration and reducing collagen content in plaques, making them more prone to rupture and triggering AMI (Organ et al., 2016). SCFAs have a protective effect on MI. The reduced level of SCFA in patients with MI (due to the decrease in SCFA-producing bacteria) weakens its anti-inflammatory and cardioprotective functions. For instance, butyrate can inhibit histone deacetylases (HDACs) in cardiomyocytes, thereby reducing oxidative stress and apoptosis. Acetate and propionate can also alleviate systemic inflammation by inhibiting the production of pro-inflammatory cytokines and enhancing the function of regulatory T cells (Bartolomaeus et al., 2019; Aguilar et al., 2014). Probiotic supplements (which can promote the generation of SCFA) can reduce the blood leptin level of myocardial infarction rats by 41%, shrink the MI area by 29%, and improve the mechanical function of the heart after ischemia by 23% (Jones et al., 2014). The cardiac function of mice after MI can also be improved by enhancing the diversity of intestinal microbiota and the generation of SCFA (Moraes-Silva et al., 2017).

Atrial fibrillation (AF), as the most common type of arrhythmia, is the second leading cause of death in many industrialized countries (Schnabel et al., 2015; Go et al., 2003). Over the past 20 years, the number of people hospitalized in the United States due to atrial fibrillation has increased by 60%. Predictions suggest that the prevalence could soar fivefold by 2050, potentially affecting 12 million Americans (Heidenreich et al., 2022). Dietary patterns are important modulatable risk factors for atrial fibrillation (Lloyd-Jones et al., 2002). A high-fat diet (HFD, which is a core component of WD) increases the risk of atrial fibrillation. Mice fed HFD showed a higher incidence and duration of atrial fibrillation, and the mRNA levels of pro-fibrotic markers (collagen 1, collagen 3, α-SMA) in the left atrium were significantly increased (Gronroos and Alonso, 2010; Fukui et al., 2017). This is closely related to more severe atrial fibrillation fibrosis—a key driver of atrial fibrillation. Similarly, if sheep consume a high-calorie diet for eight consecutive months, it will lead to a decrease in atrial fibrillation conduction velocity and an increase in inflammation, further promoting atrial fibrillation (Zhang et al., 2020). High-fat diet-induced weight gain is a major risk factor for atrial fibrillation: Adipose tissue accumulation promotes myocardial fibrosis through dysregulation of inflammatory mediators and adipokines, leading to atrial structural remodeling and chamber dilation (Abed et al., 2013; Sumeray et al., 1988; Echahidi et al., 2007). Long-term intake of high-fat and high-calorie diets is the main cause of obesity and another independent risk factor for atrial fibrillation. Rodent model studies have shown that long-term feeding of HFD can significantly increase body weight, increase atrial mass and promote myocardial cell apoptosis (Heidenreich et al., 2022). These changes alter the host's energy metabolism, leading to the accumulation of adipose tissue in obese animals and triggering atrial structural remodeling—making them more prone to atrial fibrillation (Meng et al., 2017). Diabetes (often caused by Verdi's disease) is also an independent risk factor for atrial fibrillation: a comprehensive meta-analysis shows that the incidence of atrial fibrillation in people with diabetes is 40% higher than that in non-diabetic populations (Jia et al., 2016). Experiments using animal models of diabetes further demonstrated that a diet high in fat, sugar, and cholesterol would exacerbate atrial structural remodeling and promote the occurrence of arrhythmia (Bell and Goncalves, 2019; Pacher et al., 1999). On the contrary, a beneficial dietary pattern can reduce the risk of atrial fibrillation. The incidence of atrial fibrillation among the lowland indigenous people of Bolivia (such as the Zimane and Moselten) is extremely low, which is attributed to their diet rich in dietary fiber, polyunsaturated fatty acids, potassium, magnesium, and selenium (Watanabe et al., 2012). The Mediterranean diet—characterized by a large intake of green leafy vegetables, fruits, fish and moderate amounts of wine—has a heart-protective effect on atrial fibrillation. The Mediterranean diet not only improves obesity, hypertension and dyslipidemia in patients, but also significantly reduces systemic inflammatory markers—all of which are related to the pathogenesis of atrial fibrillation (Rowan et al., 2021). These findings suggest that the risk of AF can be effectively reduced by modifying the diet to reduce high-fat and sodium intake and increase dietary fiber-rich foods.

Intestinal flora imbalance is closely related to the onset of AF. High-throughput sequencing studies (including metagenomics and metabolomics) have found that regardless of whether patients belong to the subtype of persistent atrial fibrillation (psAF) or paroxysmal atrial fibrillation (PAF), their characteristic is a decrease in microbial diversity. In addition, the numbers of key bacterial groups such as Faecobacter, Prevotella, Alistapbacterium, Actinobacter, Sartre, and Faecobacter Plusnitz decreased significantly. The genera of Butyricococcus, Flavobacterium, and Bifidobacterium also showed a similar downward trend (Svingen et al., 2013). Among them, the symbiotic butyric acid bacteria with anti-inflammatory properties—Faecobacter Plusnitz—have attracted much attention. Its deficiency is related to the pathological mechanism of inflammation, thereby promoting the occurrence of atrial remodeling and atrial fibrillation (Zuo et al., 2019). The imbalance intestinal flora is closely related to the onset of AF. High-throughput sequencing studies (including metagenomics and metabolomics) have found that regardless of whether patients belong to the subtype of psAF or PAF, their characteristic is a decrease in microbial diversity. In addition, the numbers of key bacterial groups such as Faecobacter, Prevotella, Alistapbacterium, Actinobacter, Sartre, and Faecobacter Plusnitz decreased significantly. The genera of Butyricococcus, Flavobacterium, and Bifidobacterium also showed a similar downward trend (Svingen et al., 2013). Among which, the symbiotic butyric acid bacteria with anti-inflammatory properties—Faecobacter Plusnitz—have attracted much attention. The deficiency of Faecobacter Plusnitz is related to the pathological mechanism of inflammation, thereby promoting the occurrence of atrial remodeling and atrial fibrillation (Zuo et al., 2019). Previous studies have confirmed that the numbers of Alistroplata and Oscillobacter, which are beneficial bacteria for maintaining intestinal ecological balance and reducing cardiovascular risk, also decrease in patients with atrial fibrillation, further disrupting intestinal homeostasis (Miquel et al., 2013; Nagai et al., 2010). There are also significant changes in the enterovirus group in patients with AF: a significant increase in virus diversity, accompanied by structural changes in the enterovirus population (such as increased proportion of streptococcal phage DT1 and Pseudomonas phage), and functional imbalance of enterovirus activity, especially in the membrane structure composition and metal ion binding pathway (Barber et al., 2021). These viral changes may affect the bacterial community indirectly (such as lysing beneficial bacteria) or directly act on host cells, thereby promoting the occurrence of atrial fibrillation.

TMAO is a key microbial metabolite driving the progression of AF. Intestinal flora can promote the conversion of dietary choline/carnitine into TMAO, which in turn accelerates the polarization of M1 macrophages and causes cell pyrosis, thus aggravating the remodeling of atrial structure (Patti et al., 2017; Yang et al., 2015). Multiple studies have confirmed a significant association between TMAO levels and the occurrence of AF (Rowan et al., 2021; Yu et al., 2018) suggesting that direct injection of TMAO into the ganglionated plexus of dogs induces atrial electrical remodeling through myocardial fibrosis and cardiac dysfunction, thereby promoting the induction and maintenance of AF. SCFAs plays a protective role on AF. The number of SCFA-producing bacteria (such as Faecobacter praxis and Streptococcus butyrate) in patients with atrial fibrillation decreases, leading to a drop in SCFA levels and weakening its anti-inflammatory and anti-fibrotic effects. For instance, butyrate effectively inhibits atrial fibrosis by suppressing the key driver of atrial collagen deposition—the TGF-β/Smad signaling pathway. Acetate and propionate also reduce systemic and atrial inflammation by inhibiting the production of pro-inflammatory cytokines such as TNF-α and IL-6 and enhancing regulatory T cell function (Barber et al., 2023; Aguilar et al., 2014). The absence of these protective effects will exacerbate atrial remodeling and increase susceptibility to AF. LPS may also be involved in the pathogenesis of atrial fibrillation. The imbalance of intestinal flora and intestinal barrier dysfunction in patients with AF enable LPS to enter the systemic circulation, activate the TLR4/NF-κB signaling pathway in atrial myocytes and fibroblasts, release pro-inflammatory and pro-fibrotic mediators, and trigger the occurrence of atrial inflammation and fibrosis, the key inducements of AF (Carnevale et al., 2020; Zuo et al., 2020). In addition, inflammation induced by LPS impairs electrical conduction in the atria, which increases the risk of arrhythmia.

Hyperlipidemia is a metabolic disorder characterized by lipid metabolism imbalance and is a major risk factor for atherosclerotic CVD (ASCVD) (Albrektsen et al., 2023). It is defined as elevated levels of serum total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C), while decreased levels of high-density lipoprotein cholesterol (HDL-C). Hyperlipidemia causes nearly half of global deaths (Giau et al., 2015), and its prevalence and mortality rates continue to rise (Global Burden of Disease Study Collaborators, 2017). An unreasonable diet structure, especially WD, can promote the occurrence of hyperlipidemia. High fat (21%), high cholesterol (1.5%) and carbohydrate (50%) of WD (Vasquez et al., 2012; Schierwagen et al., 2016) will accelerate key genetic factors in the lipid metabolism of apolipoprotein E (APOE) lack (Beltrán-Debón et al., 2011). APOE regulates blood lipid and lipoprotein levels through a variety of mechanisms (Giau et al., 2015), and APOE knockout mice develop severe hypercholesterolemia (“Global, regional, and country incidence, prevalence, and years lived with disability for 354 diseases and injuries, 1990–2017, in 195 countries and territories: a systematic analysis of the Global Burden of Disease Study Collaborators (2017), (2018). In WD mice, plasma TC levels were increased 3 to 7 times, and long-term exposure could increase TC levels as high as 1,200–1,400 mg/dL (Beltrán-Debón et al., 2011). Humans and animals with APOE gene defects are rich in plasma cholesterol and are more likely to develop WD and rapidly develop hyperlipidemia and atherosclerosis (Jeon et al., 2015). Phytosterols have a protective effect on hyperlipidemia: daily intake of 2 grams of phytosterols can effectively lower LDL-C levels and prevent the occurrence of hyperlipidemia. However, a typical WD contains only about 300 mg/day of phytosterols, which is insufficient to exert its protective effect (Zhang et al., 1992; Piepoli et al., 2016). Therefore, long-term adherence to WD will inevitably lead to the development of hyperlipidemia. In addition, WD can trigger oxidative stress and disrupt autophagy—a key process in lipid metabolism. In the APOE gene knockout mouse model, 7 weeks of WD feeding led to a doubling of reactive oxygen species (ROS) production in the aorta, and a more significant fourfold increase after 8 weeks (Bujak et al., 2015). ROS and other free radicals can cause imbalances in biological systems, leading to oxidative damage to cells and tissues, and increasing susceptibility to hyperlipidemia and cardiovascular complications (Judkins et al., 2010). After 12 weeks of WD feeding, oxidative stress markers in the blood and aorta significantly increased (especially in vulnerable areas), and the reduction in oxygen supply further promoted the development of hyperlipidemia (Parathath et al., 2011).

The structure and function of intestinal flora are the key factors causing hyperlipidemia. 16S rRNA gene sequencing analysis of stool samples from children and adolescents with primary hyperlipidemia revealed a significant increase in the abundance of 36 bacterial taxa (most of which belonged to the phylum Firmicutes, especially the family of Rumen Coccaceae and Christensen), while Bacteroides and Akkermenia mucinalis were significantly reduced in samples from patients with hyperlipidemia (Manco et al., 2010). Existing studies have shown that the reduction of Bacteroides and the increase of Firmicutes are important factors leading to various metabolic disorders, including obesity (Gargari et al., 2018). Compared with healthy people, the abundance of probiotics (such as Bifidobacterium, Lactobacillus, and Faecobacter plusnitz) in fecal samples of patients with metabolic syndrome complicated with hyperlipidemia was significantly reduced (Ley et al., 2006). It is well known that these beneficial bacteria play a key role in lipid metabolism: bile salt hydrolase (BSHs) produced by Bifidobacterium and Lactobacillus can uncoupling bile acids and reduce the absorption of cholesterol in the intestine, while butyrate produced by Faecobacter Plusnitz can regulate lipid metabolism and alleviate inflammation (Ley et al., 2006). The decline in the abundance of this flora in patients with hyperlipidemia will disrupt lipid homeostasis, thereby aggravating the condition. Beneficial dietary components can improve hyperlipidemia by regulating the intestinal flora. The polyphenol components in red wine can promote glucose and lipid metabolism by increasing the abundance of Enterococcus, Prevococcus, Bifidobacterium, Bacteroides, Egeria, and Brucella, while improving endothelial function and cardiac function (Agouni et al., 2009; Moreno-Indias et al., 2016). Among which, the genus Prevotella regulates cholesterol synthesis by fermenting dietary fiber to produce SCFAs. Bacteroides and Bifidobacterium reduce cholesterol absorption through β -hydroxylase (BSH) activity (Agouni et al., 2009).

Short-chain fatty acids (SCFAs) are key mediators in the regulation of lipid metabolism, and low SCFA levels in the body will accelerate the development of disease in patients with hyperlipidemia. Children and adolescents with hyperlipidemia have significantly lower levels of acetic, propionic, and butyric acid (Gargari et al., 2018). Acetic acid and propionic acid have dual regulatory effects on cholesterol metabolism: as a precursor for cholesterol synthesis in the liver, a decrease in the level of acetic acid can disrupt cholesterol homeostasis. Propionic acid, inhibit 3 - hydroxy - 3 - methyl glutaric acyl coenzyme A (HMG CoA reductase activity speed limit (cholesterol synthesis of the key enzymes) to suppress the liver cholesterol synthesis (Mohania et al., 2013). In a high-fat rat model, increased SCFA-producing bacteria significantly improved the symptoms of obesity and hyperlipidemia, which confirmed the protective effect of SCFAs (Mohania et al., 2013). In addition, TMAO and LPS are also important triggers of hyperlipidemia. The levels of TMAO and LPS in patients with hyperlipidemia are significantly elevated (Gargari et al., 2018). Among them, TMAO promotes lipid accumulation in macrophages and hepatocytes, increases the intake of LDL-C, and simultaneously inhibits cholesterol excretion mediated by HDL-C, thereby exacerbating hyperlipidemia and atherosclerosis (Organ et al., 2016). LPS activates the TLR4/NF-κB signaling pathway in hepatocytes and adipocytes, promoting the release of pro-inflammatory cytokines (such as interleukin-6, TNF-α), and further disrupting the lipid metabolism balance. For example, TNF-α can reduce the expression of low-density lipoprotein receptor in hepatocytes, thereby hindering the clearance of low-density lipoprotein cholesterol and promoting lipolysis in adipocytes, resulting in increased serum triglyceride levels (Moreno-Indias et al., 2016; Gargari et al., 2018). Regulating the intestinal flora to restore metabolic balance is an effective strategy for reversing hyperlipidemia. After supplementing garnet acid in a mouse model with a high-fructose and high-fat diet, the proportion of Muribaculaceae microbiota increased, the proportion of Blautia microbiota decreased, and the level of SCFA rose simultaneously, thereby improving the symptoms of hyperlipidemia (Queipo-Ortuño et al., 2012). Peanut polypeptides (prepared by mixed fermentation of peanut powder) can significantly enhance the diversity of intestinal flora, reduce the body weight of mice, and alleviate the negative impact of high-fat diet on lipid metabolism in hyperlipidemic mice (Mohania et al., 2013). Quercetin promotes the growth of beneficial bacteria, inhibits the reproduction of harmful bacteria, reduces the ratio of Firmicutes to Bacteroides, regulates dyslipidemia, and has a liver-protective effect (Ding et al., 2023; Velasquez and Katz, 2010).

Hypertension is a major burden on global public health. Abundant epidemiological evidence suggests that WD patterns (WD), characterized by high sodium intake (Lozano et al., 2012), high saturated fat and refined sugar intake, and insufficient dietary fiber intake, contribute to the pathogenesis of hypertension through a variety of mechanisms, including immune dysregulation, elevated plasma C-reactive protein levels, and secondary systemic inflammation (Xu and Knight, 2015). High sodium intake is a typical feature of the WD pattern and the main pathogenic factor of hypertension (Rust and Ekmekcioglu, 2017). Dietary sodium exerts its hypertensive effect by regulating the composition of the intestinal flora and disrupting microbiota-inflammatory homeostasis. Epidemiological data show that the dietary pattern characteristic of WD patterns over the past three decades is strongly associated with a significant increase in refined sugar intake (Rust and Ekmekcioglu, 2017). Clinical studies have shown that after consuming sweet beverages containing glucose and fructose, cardiac rate, cardiac output and blood pressure all significantly increase within 2 h (Popkin and Nielsen, 2003). In animal models, a long-term intake of high saturated fat and sugar in the WD pattern can cause persistent systolic hypertension. These dietary patterns exacerbate aortic stiffness and inhibit endothelium-dependent vasodilation, which is a key mechanism of obesity-related metabolic and vascular dysfunction (Brown et al., 2008; Hannou et al., 2018). Transcriptome analysis of mice fed HFD diet revealed that the expansion of visceral adipose tissue (VAT) was an independent risk factor for the onset of hypertension. Visceral adipose tissue, as an active endocrine organ, can secrete pro-inflammatory cytokines (for example, factors such as tumor necrosis factor -α (TNF-α) and interleukin-6 (IL-6) can cause arterial endothelial dysfunction, promote lipid deposition, and drive fibrotic changes. These mechanisms can disrupt normal vascular homeostasis and blood pressure regulation (Padilla et al., 2015; Gibson et al., 2007). Under normal circumstances, vascular endothelium regulates vascular tension by balancing the release of vasoactive mediators, including vasodilators (such as nitric oxide NO) and vasoconstrictors (such as angiotensin II) (Su et al., 2024). In mouse models, VAT hypertrophy induced by angiotensin II receptor shows significant upregulation of Spp1, angiotensin II and Postn expression. These molecular changes are associated with impaired vasodilation function, increased vascular stiffness and enhanced fibrotic remodeling, jointly promoting the development of hypertension (Gonzalez and Selwyn, 2003).

A meta-analysis of clinical trials has shown that probiotic fermented milk significantly reduces systolic and diastolic blood pressure in patients with hypertension (Wang et al., 2023). Comprehensive metagenomic and metabolomic analysis revealed that the microbial richness and diversity in patients with hypertension were significantly reduced (Li et al., 2017). After transplanting the fecal microbiota of hypertensive patients into germ-free mice, significant deficiencies were observed at the levels of Anaerotruncus, Coprococcus, Ruminococcus, Clostridium, Roseburia, Blautia, and Bifidobacterium. These findings are consistent with the results of previous metagenomic analyses (Dong et al., 2013; Li et al., 2017; Yang et al., 2015). Reverse transcription quantitative polymerase chain reaction (RT-qPCR) technology has filled the gap in the research on the distribution of intestinal flora in patients with hypertension. The positive association of rectal Bacteroides with systolic and diastolic blood pressure and the negative association of Bacteroides and Bifidobacterium strongly confirm the direct and significant association between gut microbiota and hypertension (Gargari et al., 2018). Animal model studies have further confirmed the imbalance of intestinal flora in patients with hypertension. All animal models of hypertension showed dysbiosis of intestinal flora, with a significant reduction in the number of SCFA-producing bacteria (Yan et al., 2017). For example, in the rat fecal model induced by chronic angiotensin II (Ang II) infusion, the number of bacteria producing acetic acid and butyrate decreased significantly (Bier et al., 2018). In the rat model of hypertensive apnea syndrome, the number of Lactobacillus increased, while the population of Lactobacillus butyrate, which converts lactic acid into butyric acid, decreased exponentially (Yang et al., 2015). The changes in these SCFA-producing bacteria lead to a decrease in SCFA levels, thereby weakening its blood pressure-lowering effect.

Short-chain fatty acids (SCFAs) are key microbial metabolites that regulate blood pressure—a decline in their levels is closely related to the onset of hypertension. Butyrate can alleviate the pro-inflammatory effect caused by LPS stimulation (Gargari et al., 2018), and effectively lower blood pressure (Wright et al., 1990). Acetate and propionate both have the effect of regulating blood pressure: acetate can enhance the production of nitric oxide (NO) in endothelial cells and promote vasodilation; Propionate inhibits sympathetic nerve activity and reduces vascular resistance (Aguilar et al., 2014). A high-fiber diet lowers blood pressure by increasing the concentrations of Bacteroides and acetate in the intestinal tract, confirming the antihypertensive effect of SCFAs (Durgan et al., 2016). LPS plays an important role in the pathogenesis of hypertension. The intestinal flora imbalance and intestinal barrier dysfunction in patients with hypertension enable LPS to enter the systemic circulation and activate the TLR4/NF-κB signaling pathway in vascular endothelial cells and smooth muscle cells. This will trigger the release of pro-inflammatory cytokines (such as interleukin-1 β, TNF-α, interleukin-6, IL-6), leading to impaired endothelial function—reducing NO production and causing vasoconstriction. LPS can also promote the proliferation and migration of vascular smooth muscle cells, leading to vascular remodeling and increased vascular stiffness, thereby further raising blood pressure (Gargari et al., 2018; Lozano et al., 2012). TMAO may also play an important role in hypertension. Elevated TMAO levels in patients with hypertension (caused by intestinal flora imbalance resulting from WD) can enhance platelet hyperreactivity and promote vascular inflammation, thereby exacerbating hypertension and its complications (Chen et al., 2025; Zhu et al., 2017). TMAO also impairs endothelial function by reducing the bioavailability of NO, further exacerbating vasoconstriction and elevated blood pressure. Increasing the level of SCFA may become a potential therapeutic strategy for blood pressure management. Studies have shown that increasing SCFA production through high-fiber diets, probiotic supplements, and prebiotic supplements has demonstrated blood pressure-lowering effects in both human and animal experiments (Bier et al., 2018). For instance, probiotic-fermented milk can lower blood pressure in patients with hypertension (Chen et al., 2025), while a high-fiber diet can reduce blood pressure by increasing SCFA levels (Durgan et al., 2016). These findings highlight the potential value of targeting the gut microbiota and SCFA metabolism in the prevention and treatment of hypertension (see Figure 3; Table 1).