Amid socioeconomic development, lifestyle transformations are driving an increased prevalence of overweight or obesity and associated health risks globally (Zhou et al., 2024). This constitutes a pressing health challenge, irrespective of the nation’s development status (Wong et al., 2020). Obesity pathogenesis involves multifaceted mechanisms, with research indicating that gut microbiota dysbiosis-induced metabolic dysregulation and functional decline may be key contributors (Geng et al., 2022). The scientific importance of the gut mycobiome (Zhan et al., 2024) is attracting increasing attention.

An early study (Gouba et al., 2013) ‌identified eight fungal genera, including Aspergillus, Penicillium, and Malassezia, in the gut of obese women using polymerase chain reaction amplification and fungal culture, ‌suggesting‌ a potential role for fungi in host metabolism. Subsequent studies have established the structural features of the gut mycobiome in obese individuals, revealing that fungal diversity is significantly reduced (Szóstak et al., 2023) and that alterations in specific genera are correlated with metabolic parameters.‌ Specifically, Mucor abundance was decreased in obese individuals (Mar Rodríguez et al., 2015), while levels of Candida, Saccharomyces cerevisiae, and Penicillium correlated positively with body weight, body mass index (BMI), and waist circumference (Salamati et al., 2015; Borges et al., 2018; García-Gamboa et al., 2021; Shoukat et al., 2023).‌ In an infant cohort study,‌ Saccharomyces ‌demonstrated potential relevance, with its abundance positively correlating with BMI and potentially predicting childhood obesity risk (Gutierrez et al., 2023). Another study found a significantly elevated phylum-level abundance of Mortierellomycota in metabolically healthy obese individuals, suggesting a potentially protective role (Yin et al., 2022).‌ Roux-en-Y gastric bypass, known for its effectiveness in treating obesity, can help in reestablishing mycobiome balance. Post-surgery reductions in the abundance of Candida and Saccharomyces have been observed in obese individuals (Steinert et al., 2020). Candida species, such as C. albicans and C. parapsilosis, contribute to obesity induced by a high-fat diet by elevating intestinal free fatty acid levels (García-Gamboa et al., 2021; Sun et al., 2021).

Animal models play a vital role in examining how the gut mycobiome is causally related to obesity. A high-fat diet impacts the gut bacterial community in mice and significantly suppresses the abundance of beneficial fungi (Heisel et al., 2017). Furthermore, antifungal treatment that disrupts the mycobiome exacerbates metabolic disorders in these models (Abdallah et al., 2020). Moreover, early colonization by specific fungi exerts a long-term impact on metabolic outcomes. Studies demonstrate that Rhodotorula mucilaginosa and Malassezia restricta promote obesity and the progression of metabolic disorders in mice (Gutierrez et al., 2025). ‌Conversely, several interventions, including a low-carbohydrate diet (Yu et al., 2022), Litchi chinensis seed (Xiang et al., 2022), and avenanthramide B (Liu et al., 2025), can reverse obesity progression. These interventions promote weight loss by rebalancing the ratio of beneficial to pathogenic fungi.

In summary, elevated abundance of Candida spp., Saccharomyces cerevisiae, Penicillium spp., Rhodotorula mucilaginosa, and Malassezia restricta may be involved in the development and onset of obesity. Conversely, Mortierellomycota and Mucor spp. may confer potential protective roles against obesity (Table 1).

Diabetes mellitus is identified as a metabolic disorder with either an absolute or relative shortage of insulin and/or resistance to insulin in the organs it affects (American Diabetes Association, 2014). It can lead to various vascular and peripheral neuropathic complications, severely impairing the quality of life of affected individuals worldwide (Ahmad et al., 2022). Established risk factors, including genetics, family history, and metabolic dysregulation, have been demonstrated to play substantial roles in the development and progression of diabetes (Yu et al., 2024). ‌Recent research has elucidated a close association between gut microbiota and diabetes (Gurung et al., 2020; Zhou et al., 2022). A landmark study published in Science demonstrated that early-life exposure to C. dubliniensis during infancy confers protection against diabetes development (Hill et al., 2025). This study utilized human infant fecal samples to colonize murine models, revealing that mice colonized with samples from infants aged 7–12 months exhibited significantly elevated insulin expression in pancreatic islets and increased circulating serum insulin levels. Subsequent mechanistic investigations demonstrated that cell wall components derived from fungi such as Aspergillus dublinensis induce infiltration of islet-resident macrophages (IRMs) and promote β-cell regeneration in diabetic murine models, thereby attenuating diabetes incidence (Hill et al., 2025). These results further scientific insights into the involvement of the gut mycobiome in diabetes development.

Previous studies have consistently documented reduced diversity in gut fungal communities among individuals with type 2 diabetes mellitus (T2DM) (Yan et al., 2024; Gou et al., 2024; Van Syoc et al., 2024). This dysbiotic pattern is markedly exacerbated in patients with diabetic complications such as diabetic foot ulcers (Cai et al., 2024). A parallel reduction in mycobiome diversity has been observed in the cohorts of type 1 diabetes (T1DM) and gestational diabetes mellitus (GDM) (Bandala-Sanchez et al., 2022; Vavreckova et al., 2022). This evidence indicates that gut mycobiome dysbiosis, characterized by diminished diversity, is a common pathophysiological feature across subtypes of diabetes mellitus. Investigations into signature fungal taxa have revealed significant enrichment of the genus Candida across all major forms of diabetes mellitus. Studies have demonstrated significantly elevated intestinal Candida burden in patients with T2DM compared to healthy controls (Bao et al., 2023; Saleem et al., 2022; Jayasudha et al., 2020; Al Bataineh et al., 2021; Bhute et al., 2017; Rodrigues et al., 2019; Gosiewski et al., 2014). Further reinforcing this observation, research indicates that microbial translocation occurs between oral and gut microbiomes in diabetic populations (Pacheco-Yanes et al., 2023), correspondingly increasing Candida abundance in the oral cavity (Mussi et al., 2022). ‌Animal model studies have further demonstrated increased intestinal Candida colonization in diabetic dogs (Jaffey et al., 2022) and mice (Zhang et al., 2025). Moreover, Candida colonization rates are significantly higher in patients with T1DM (Honkanen et al., 2020; Gürsoy et al., 2018; Soyucen et al., 2014) and gestational diabetes (Vavreckova et al., 2022) than in healthy subjects. These findings suggest that aberrant Candida proliferation may represent a potential microbial marker for the pathogenesis of diabetes mellitus. Yeasts have also demonstrated significant potential in diabetic populations. The intestinal abundance of Rhodotorula mucilaginosa is closely associated with disease progression in T2DM studies (Cai et al., 2024), while alterations in Saccharomycetes class abundance correlate with the response to metformin treatment in patients with T2DM (Van Syoc et al., 2024). Cohort studies have revealed that Saccharomyces enrichment strengthens the association between conventional risk factors (obesity and insulin resistance) and T2DM, suggesting its potential as a predictive biomarker (Gou et al., 2024). In GDM research, changes in the abundance of taxa, such as Hanseniaspora, directly correlate with dysglycemia (Wu et al., 2022). Conversely, late-pregnancy intestinal enrichment of Saccharomyces cerevisiae in T1DM mothers frequently coincides with elevated inflammatory markers (Bandala-Sanchez et al., 2022). Similarly, aberrant Saccharomyces proliferation in children with T1DM is associated with pancreatic autoimmunity and intestinal inflammation. These findings further implicate Saccharomycetes in the pathogenesis of diabetes (Honkanen et al., 2020). ‌Furthermore, elevated intestinal levels of Fusarium and Malassezia furfur in patients with T2DM underscore the disease-specific signatures within the mycobiome. Regarding interventions, 12-week exercise training ameliorated insulin resistance by enriching beneficial fungi such as Verticillium (Wang et al., 2024). Additionally, Echinacoside suppresses hepatic gluconeogenesis by remodeling bacterial-fungal interaction networks (Fan et al., 2025), while exogenous H2S improves metabolism by reducing the abundance of Candida and Aspergillus (Liu et al., 2022). These approaches provide novel therapeutic avenues for precise interventions.

‌Reduced gut mycobiome diversity and increased abundance of genera, including Candida, Saccharomyces, and Hanseniaspora, may contribute to diabetes progression, whereas exercise-induced enrichment of Verticillium demonstrates potentially protective roles in diabetes amelioration (Table 2).

‌AS is a prevalent condition that poses a substantial threat to human health, with coronary artery disease as a primary manifestation. A hallmark feature of AS lesions is the subendothelial accumulation of lipids within specific arterial regions, accompanied by smooth muscle cell proliferation and deposition of fibrous matrix components, resulting in atherosclerotic plaque formation (Shao et al., 2024). When AS affects coronary arteries, complete vascular occlusion can occur, potentially triggering myocardial infarction. Similarly, obstructions in cerebral vessels can cause cerebral infarction, commonly termed as a stroke. This pathological process constitutes the fundamental pathological basis of ischemic cardiocerebrovascular diseases (Lu and Daugherty, 2015). AS pathogenesis involves multifactorial complexity. Previous studies indicate that relevant theories primarily involve inflammation (Wolf and Ley, 2019), lipid accumulation (Bäck et al., 2019), oxidative stress (Batty et al., 2022), and endothelial injury; however, no single theory fully accounts for the entire pathogenesis of AS. ‌Beyond the established risk factors, hypertension, diabetes, hypercholesterolemia, smoking, stressors, and environmental determinants significantly accelerate lesion progression (Libby, 2021). Epidemiological data have confirmed that AS is a principal contributor to global cardiovascular mortality and morbidity. In Western populations, AS-related deaths constitute approximately 50% of all cardiovascular fatalities (Ramji and Davies, 2015). Consequently, elucidating AS pathogenesis and developing targeted therapeutic strategies have substantial clinical and scientific implications.

‌Early investigations have established a direct link between fungi and AS. In 2007, a study employing fungal rDNA detection within coronary plaques initially identified mycotic components in atherosclerotic lesions (Ott et al., 2007). Subsequent research further identified detectable C. albicans DNA even in non-atherosclerotic aortic walls, with a significant correlation with vascular inflammation marker expression (Jegier et al., 2010). Masoumi and Nurgeldiyeva et al. substantiated the presence of Candida spp. within plaques and proposed their potential role in promoting atherogenesis by inducing vascular inflammation (Masoumi et al., 2015; Nurgeldiyeva et al., 2014). These findings provide the initial evidence of fungal involvement in the pathological progression of AS.

Recent research has increasingly focused on the interplay between the gut mycobiome and host lipid metabolism dysregulation, as well as its impact on atherogenesis. Empirical evidence reveals an inverse correlation between gut fungal diversity indices and triglyceride (TG) levels, suggesting that diminished mycobiotic diversity may contribute to pathological lipid accumulation (Estrada et al., 2024). ‌Alterations in the abundance of intestinal genera, including Candida, Thermomyces, and Saccharomyces, correlated significantly with lipid metabolism dysregulation (Mims et al., 2021). C. albicans has emerged as a primary pathogenic driver, exhibiting an elevated abundance in patients with dyslipidemia. Research has demonstrated that its metabolic byproduct, formyl-methionine, provokes aberrant lipid metabolism and promotes plaque development (Wang et al., 2024). Furthermore, patients with atherosclerotic CVD exhibited significantly increased abundances of the genera Exophiala and Malassezia (Su et al., 2025). However, contradictory findings have emerged in patients with coronary heart disease, where a decreased abundance of these fungal taxa has been observed (Xu et al., 2020). This suggests that a structural imbalance in the gut mycobiome may potentiate AS progression, concurrently underscoring the importance of further clinical validation. Abundances of Mucor racemosus (Chacón et al., 2018) and Fusarium spp. (An et al., 2024) reduced significantly, demonstrating negative associations with AS risk, thereby suggesting their therapeutic potential as protective fungal taxa. ‌In clinical intervention studies, patients undergoing coronary artery bypass grafting altered significantly gut mycobiome, characterized by decreased Schizosaccharomyces pombe and increased Saccharomyces cerevisiae abundance. These shifts suggest that surgical intervention may modulate fungal communities and influence postoperative prognosis (Fu et al., 2025). Regarding pharmacological interventions, Coptis chinensis ameliorates lipid metabolism disorders by modulating Thermomyces spp. and Saccharomyces spp., revealing its dual-targeting potential toward gut bacteria and fungi (Yang et al., 2022). This provides preliminary evidence for future fungus-targeted therapeutics.

Intestinal Candida spp., Thermomyces spp., and Saccharomyces spp. may constitute key drivers of AS progression, whereas Mucor racemosus and Fusarium spp. may represent protective fungal taxa (Table 3).

Hypertension is a cardiovascular syndrome characterized by sustained elevation of systemic arterial pressure. This condition poses significant risks for a spectrum of cardiocerebrovascular diseases, including stroke, coronary heart disease, and HF. According to the first Global Report on Hypertension released by the World Health Organization in 2023, data from 2019 revealed that 33% of the global population aged 30–79 years had hypertension. Approximately 10 million deaths annually are attributable to elevated systolic pressure (Kario et al., 2024). Studies have confirmed that overweight, obesity, dyslipidemia, and insulin resistance are established risk factors for hypertension (Tang et al., 2022; Guo et al., 2025), with metabolic disorders contributing to over half of hypertension cases while directly promoting vascular dysfunction and blood pressure elevation (Zhu et al., 2016).

Emerging research has revealed that the gut mycobiome mediates metabolic dysregulation and elevates blood pressure. Despite the absence of statistically significant differences in gut mycobiome diversity between hypertensive patients and healthy controls (Qiu et al., 2023; Zou et al., 2022), specific alterations in fungal abundance are significantly associated with blood pressure regulation. Malassezia demonstrated significant enrichment in hypertensive cohorts, and its abundance positively correlated with serum immunoglobulin light chain (κ/λ) concentrations. This implicates its pathogenic role in hypertension via immune activation (Zou et al., 2022). Conversely, Mortierella prevails predominantly in normotensive populations (Zou et al., 2022), presenting an inverse association with homocysteine, an established hypertension biomarker, suggesting a protective function through metabolic modulation (An et al., 2024). Several species of Exophiala (E. xenobiotica and E. mesophila) demonstrated direct positive correlations with systolic and diastolic blood pressure levels. Concurrently, patients with hypertension exhibit dysbiosis in shared fungal communities across gut-oral axes (Chen et al., 2023). Furthermore, the genera Nakaseomyces and Saccharomyces are specifically associated with diastolic pressure (Qiu et al., 2023).

‌The genera Malassezia, Exophiala, Nakaseomyces, and Saccharomyces demonstrate pathophysiological contributions to blood pressure elevation, whereas Mortierella potentially confers protective cardiometabolic benefits (Table 4).

‌HF is a clinical syndrome primarily driven by structural and/or functional cardiac abnormalities. This pathophysiological cascade elevates the intracardiac pressures at rest or during exertion and/or compromises cardiac output, manifesting as diverse clinical symptoms (McDonagh et al., 2021). HF is an end-stage manifestation of CVD, including hypertension, and is intrinsically linked to cardiac decompensation. Despite prolonged investigations into the association between HF progression and gut microbiota alterations (Sandek et al., 2007), a definitive causal link remains unestablished (Tang et al., 2019).

A prior Mendelian randomization analysis revealed no genetic causal relationship between C. albicans gut colonization and HF pathogenesis (Luo et al., 2022), whereas discordant conclusions have emerged from independent cohort studies. Animal studies have demonstrated that in C5-deficient mice, gut-derived C. albicans infection directly triggers cardiac inflammatory damage and metabolic dysregulation, ultimately culminating in heart failure (Mullick et al., 2006). Clinical investigations have revealed a significant proliferation of pathogenic fungi, including Candida spp., in the gut mycobiome of patients with chronic heart failure (CHF), concomitant with elevated intestinal permeability and systemic inflammation. These alterations are positively correlated with disease severity, further supporting the association between gut mycobiome dysbiosis and HF progression (Pasini et al., 2016). Moreover, heightened inflammatory cytokine levels in CHF may compromise immune function and increase susceptibility to pathogenic fungal overgrowth (García-Torre et al., 2021). This provides evidence of a complex, mutually reinforcing relationship between HF and gut mycobiome perturbations involving immune competence, medication exposure, and inflammatory status. Therapeutically, targeted probiotic supplementation (Saccharomyces boulardii) failed to improve cardiac function or microbial diversity in the GutHeart trial (Awoyemi et al., 2021), indicating complexity in microbiota modulation strategies.

Gut mycobiota, particularly Candida spp., could be crucial in the beginning and advancement of HF (Table 5). However, current evidence remains limited, warranting further in-depth investigations.

‌MetS is a pathological state characterized by dysregulated metabolism of carbohydrates, lipids, and proteins. Its four core features are obesity, dyslipidemia, hepatic steatosis, and insulin resistance (Ndumele et al., 2023). Globally, MetS affects approximately 25% of the population and contributes to two-thirds of noncommunicable disease-related mortality, and its prevalence continues to rise worldwide (Saklayen, 2018). Evidence suggests an association between MetS and gut mycobiome dysbiosis.

Previous clinical investigations have demonstrated that the enrichment of C. albicans in the gut induces insulin resistance in obese patients with MetS, potentially serving as a key mediator linking metabolic dysregulation and immune imbalance (Nikolic et al., 2022). Further studies revealed that vitamin D3 deficiency may drive opportunistic fungal overgrowth, including Candida spp., thereby increasing the susceptibility of patients with psoriasis to MetS (Marchlewicz et al., 2024). This association is more pronounced in pregnant women, whose MetS correlates with gut microbial dysbiosis characterized by overgrowth of pathogenic fungi (C. albicans) and reduced abundance of Bifidobacterium and Lactobacillus (Pavlovska et al., 2020). Additionally, elevated gut fungal burdens of Saccharomyces and Aspergillus spp. have been documented in patients with MetS (Gradisteanu Pircalabioru et al., 2022). In parallel, dysregulation of adipokines constitutes another central feature of MetS. Pro-inflammatory adipokines such as TNF-α, IL-6, leptin, and resistin are upregulated, whereas anti-inflammatory adipokines including adiponectin and omentin are downregulated. This imbalance drives chronic low-grade inflammation, insulin resistance, and vascular dysfunction. Emerging evidence suggests that gut fungal dysbiosis, particularly Candida overgrowth, may exacerbate this adipokine imbalance by promoting systemic inflammation and thereby worsening metabolic and cardiovascular complications (Datta et al., 2025). ‌Regarding probiotic fungal interventions, the administration of Saccharomyces boulardii improves insulin sensitivity and ameliorates lipid metabolic disorders in patients with MetS by suppressing pathogenic fungal overgrowth (Egea et al., 2023).

The evidence suggests that C. albicans might play a vital role in the pathogenesis of MetS; however, the implications of Saccharomyces and Aspergillus spp. require further mechanistic substantiation (Table 6).

MAFLD is a chronic metabolic stress-related liver injury in genetically predisposed individuals, primarily driven by overnutrition and insulin resistance (Targher et al., 2024). Currently, the most prevalent chronic liver disorder has historically been termed non-alcoholic fatty liver disease (NAFLD) (Eslam et al., 2020). It has been redefined to emphasize its pathogenic links to T2DM dysregulation, involving multifaceted factors such as obesity and T2DM (Jurek et al., 2025). The growing exploration of gut microbial ecosystems further implicates mycobiome dysbiosis in MAFLD pathogenesis.

‌Accumulating evidence suggests that intestinal mycobiome dysbiosis occurs in patients with MAFLD. Fungal compositional analyses demonstrated an elevated abundance of multiple fungal taxa in NAFLD-affected guts, alterations that may drive hepatic injury, dysregulated lipid metabolism, and disease progression (You et al., 2021). Dysbiosis within the genus Candida is particularly prominent, with C. albicans and C. krusei significantly increased in MAFLD cohorts (Demir et al., 2022; Zhang et al., 2024; Hrncir et al., 2024). The increased abundance of C. albicans further serves as a biomarker for progression from fatty liver or cirrhosis to early-stage hepatocellular carcinoma (Jiang et al., 2024). Intestinal Pichia kudriavzevii and Candida spp. have been demonstrated to endogenously generate ethanol and TG via fructose-dependent pathways, directly contributing to non-alcoholic steatohepatitis pathogenesis (Mbaye et al., 2022). Concurrently, the abundance of genus Mucor is correlated with hepatic inflammation and fibrosis, with the subspecies Mucor ambiguus demonstrating significant associations with obesity, dyslipidemia, and liver injury biomarkers (Demir et al., 2022; Viebahn et al., 2024; Niu et al., 2023). Environmental and dietary risk factors further exacerbate mycobiome dysbiosis. For instance, a high-fat diet combined with chronodisruption (chronic jet lag) disrupts microbial circadian oscillations, elevates Rhodotorula and Cyphellophora spp., and reduces Aspergillus and Penicillium spp., thereby aggravating fatty liver pathology (Zheng et al., 2023). ‌Moreover, high-fructose intake amplifies the abundance of Candida spp. by remodeling bacterial-fungal cross-kingdom networks, mediating host metabolic dysfunction, and elevating the MAFLD risk (Hrncir et al., 2024). Therapeutically, the intestinal fungus Fusarium foetens exerts hepatoprotective effects against metabolic dysfunction-associated steatohepatitis by secreting bioactive secondary metabolites (Zhou et al., 2025). Concurrently, the phytochemical paeonol demonstrates therapeutic potential by ameliorating histopathological injury by remolding mycobiome dysbiosis (Wu et al., 2020; Ge et al., 2021).

‌In summary, Candida spp., Mucor spp., Pichia kudriavzevii, and other Candida yeasts correlated positively with MAFLD progression, whereas Fusarium foetens exhibited protective potential (Table 7).

The gut mycobiome directly participates in host metabolism and modulates physiological processes through its derived metabolites. Gut microbial enzymes represent an emerging research focus, as they catalyze metabolic reactions that enhance the breakdown and absorption of nutrients (Jiang et al., 2024). Recent evidence has indicated that the gut microbiota and their enzymatic derivatives significantly drive the progression of T2DM (Wang et al., 2023) and MAFLD (Luo et al., 2025). Candida parapsilosis secretes lipases that hydrolyze dietary fats, thereby elevating circulating FFA concentrations (Sun et al., 2021). FFA accumulation promotes obesity through multiple pathways, primarily by inducing inflammation that disrupts intestinal barrier integrity, secondarily by enhancing energy absorption and surplus in the gut, and ultimately by activating fat-storage pathways while inhibiting fatty acid oxidation, thereby promoting adiposity and hepatic steatosis, collectively exacerbating cardiometabolic burden (Sun et al., 2021). Furthermore, excessive fructose intake has been definitively linked to an elevated risk of CMD (Zhang et al., 2020; Soleimani et al., 2023; Drożdż et al., 2021). High-fructose diets alter bacterial-fungal cross-kingdom interactions, significantly enriching Candida spp. and Saccharomyces (Hrncir et al., 2024). These proliferating gut fungi metabolize fructose to ethanol while driving de novo TG synthesis. Both endogenously generated ethanol and TG accelerate MASLD development (Mbaye et al., 2022).

Research has established that the intestinal fungome and bacteriome maintain homeodynamic equilibrium through reciprocal modulation, collectively preserving gut ecosystem stability (Underhill and Iliev, 2014; Elnagar, 2024). This interaction mainly manifests as competition for nutrients, co-metabolism of dietary components, or modulation of the host immune system (Santus et al., 2021). Moreover, gut fungi can inhibit bacterial colonization. For example, the presence of Candida albicans reduces the efficacy of fecal microbiota transplantation (FMT) in treating Clostridioides difficile infection, and further studies have shown that Candida albicans suppresses bacterial engraftment (Zuo et al., 2018). Conversely, gut bacteria can also inhibit fungal proliferation; for instance, colonization by Lactobacillus has been shown to suppress the expansion of Candida (Strus et al., 2005). Moreover, gut fungi and bacteria not only antagonize each other, but also cooperate to promote pathogenesis. For example, Escherichia coli enhances the invasion of Candida albicans into intestinal epithelium in an in vitro model (Yang et al., 2016); another study showed that monocolonization with gut fungi alone does not induce physiological changes in germ-free mice, whereas co-colonization with fungi and bacteria significantly exacerbates colonic inflammation. These findings further highlight that the interaction between fungi and bacteria is fundamental to the onset and progression of disease (Zhang et al., 2022; Krüger et al., 2019). It is well known that diet and lifestyle, as major modifiable factors of CMD, are among the most effective regulators of microbial community interactions (Guiducci et al., 2023). Studies show that a high-fat diet is associated with increased abundance of Candida and decreased abundance of Prevotella (Heisel et al., 2017; Peroumal et al., 2022). High-carbohydrate diets show a positive correlation with elevated abundances of Candida and Methanobrevibacter (Hoffmann et al., 2013). Furthermore, high-fat, high-fructose diets (HFFD) increase the abundance of pathogenic fungi (Aspergillus, Penicillium, and Candida), while reducing the abundance of bacterial taxa including Lachnospiraceae_NK4A136_group and Harryflintia (Zhao et al., 2024; Zhao et al., 2025). Moreover, many of these bacteria with reduced abundance are probiotics capable of producing short-chain fatty acids (SCFAs), and the association between decreased SCFA levels and CMD has been extensively studied and well established (Neves et al., 2015; Wang et al., 2025). These findings confirm that diet-induced alterations in fungal and bacterial communities are closely associated with host metabolic dysregulation (glucose and lipid metabolism) and vascular inflammatory phenotypes (Zhao et al., 2024; Zhao et al., 2025). Furthermore, circadian disruption, an emerging cardiometabolic risk factor, worsens hepatic inflammation and lipid metabolism dysregulation by perturbing gut mycobiota-bacteriome interactions during chronic jetlag (Zheng et al., 2023). These findings indicate that dysregulation of the fungal-bacterial interaction network impairs microbial regulation of host energy harvest and immune homeostasis, thereby triggering inflammation due to intestinal barrier defects, as well as abnormalities in short-chain fatty acid and bile acid metabolism (Wang et al., 2020), ultimately driving the pathological progression of CMD. Further fungal transplantation experiments have reinforced this understanding. For instance, single gavage administration of Candida albicans increased the relative abundance of Staphylococcus and Mucispirillum, while decreasing the abundance of Akkermansia. Staphylococcus may produce LPS, which can enter the bloodstream through a compromised intestinal mucosal barrier, thereby triggering chronic low-grade inflammation—a key mediator in the development of insulin resistance, diabetes, obesity, and atherosclerosis (Bao et al., 2023). Furthermore, multiple studies have confirmed that supplementation with Akkermansia can ameliorate cardiometabolic diseases (Gofron et al., 2024; Niu et al., 2024), while a reduction in Akkermansia abundance further exacerbates disease pathogenesis. Although existing evidence supports the synergistic role of opportunistic fungal proliferation alongside harmful bacterial overgrowth and beneficial bacterial suppression in the pathogenesis of cardiometabolic diseases, it remains unclear whether gut fungi and bacteria also modulate CMD progression through antagonistic interactions—a question that represents a promising avenue for future research.

Gut mycobiome drives metabolic dysregulation by modulating the immune system. First, gut fungal-derived metabolites (including candidalysin, prostaglandins, formyl-methionine [Wang et al., 2024), leukotrienes, and ethanol (Santelmann and Howard, 2005; Noverr et al., 2002; Tan et al., 2019)] can induce inflammatory responses. For example, candidalysin is a fungal peptide toxin secreted by Candida albicans that directly induces IL-1α, IL-1β, IL-8, IL-36, and the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome (Zhou et al., 2024). These inflammatory mediators are known to play critical roles in the development of insulin resistance, T2DM, obesity, vascular endothelial injury, atherosclerosis, and NAFLD (Li et al., 2025). Prostaglandins (PGs) are a class of eicosanoids, comprising homologs from series 1, 2, and 3. Studies indicate that gut fungi such as Cryptococcus neoformans and Candida albicans can secrete prostaglandins via de novo synthesis or through the conversion of exogenous arachidonic acid (Noverr et al., 2001). Among these, PGE₂ has been most extensively studied and participates in regulating diverse physiological and pathological processes, associated with diseases such as diabetes, hypertension, obesity, non-alcoholic fatty liver disease, and cardiovascular diseases (Wang et al., 2021). On one hand, PGE₂ binds to the EP3 receptor to activate extracellular signal-regulated kinase 1/2 (ERK1/2), thereby inducing serine phosphorylation of insulin receptor substrate 1 (IRS1) and ultimately exacerbating insulin resistance (Henkel et al., 2009). On the other hand, PGE₂ induces β-cell dysfunction via the IL-1β-mediated NF-κB activation pathway and promotes hepatic lipid accumulation through NF-κB signaling (Chung et al., 2015). In summary, PGE₂ effectively mediates NF-κB pathway activation and dysregulation of glucose and lipid metabolism, triggering a cascade of pathological alterations in vascular endothelium (Xu et al., 2020), liver, and adipose tissue, thereby driving the progression of cardiometabolic diseases. Formyl-methionine is a metabolite that can be produced by Candida albicans (Wang et al., 2024). Studies show that the concentration of formyl-methionine in circulation is closely associated with the risk of various cardiovascular diseases (Cai et al., 2021). This substance can activate the HIF-2α signaling pathway in the gut, thereby promoting ceramide synthesis and ultimately accelerating the progression of atherosclerosis (Wang et al., 2024). Previous studies have demonstrated that ceramide, an emerging compound, is closely associated with CMD (Wilkerson et al., 2024). This bioactive lipid can induce insulin resistance, oxidative stress, and atherosclerotic plaque progression (Spaggiari et al., 2024). Secondly, gut fungi can also induce inflammatory responses through cell wall components. Upon recognition by host pattern recognition receptors (PRRs), their cell wall components (chitin, mannans, and β-glucans) trigger inflammatory cascades that exacerbate metabolic disorders (Cheng et al., 2011; Gringhuis et al., 2012). For instance, Rhodotorula mucilaginosa and Malassezia restricta, when recognized by host PRRs, drive pathological lipid accumulation by inducing intestinal low-grade inflammation and enhancing nutrient uptake, thereby promoting high-fat diet-induced obesity (Gutierrez et al., 2025). Fungal β-glucans translocate across damaged intestinal barriers, bind to the CLEC7A receptor on Kupffer cells, and trigger IL-1β-dependent hepatic inflammation and fibrosis (Yang et al., 2017), subsequently accelerating the progression of steatohepatitis. Similarly, in mouse models, Candida albicans-derived β-glucans released via the dectin-1 receptor activate inflammatory cascades to induce insulin resistance; conversely, eliminating C. albicans or blocking this pathway significantly alleviates insulin resistance and halts the progression of metabolic disorders (Bao et al., 2023). The aforementioned mechanistic studies reinforce the causal link between gut fungi and CMD. Gut fungal derivatives promote the pathogenesis and progression of metabolic cardiovascular disorders via immunoinflammatory mechanisms, as well as through pathways inducing insulin resistance and lipid metabolic disorders. Furthermore, the roles of gut bacterial derivatives—such as bile acids, LPS, and trimethylamine N-oxide (TMAO)—in CMD have been well-established (Kondapalli et al., 2025; Du et al., 2025). However, whether metabolites derived from bacteria and fungi exert synergistic or antagonistic effects in CMD remains unclear, and their interactive mechanisms warrant further elucidation in future studies.

Targeted modulation of gut fungi and their derivatives holds therapeutic promise for the integrative management of cardio-metabolic diseases. First, previous studies have demonstrated that pharmacological ablation of C. albicans using conventional antifungals (amphotericin B or fluconazole) significantly ameliorates insulin resistance and metabolic derangements (Wang et al., 2024). Fluconazole monotherapy also exhibits promising efficacy in attenuating AS progression by suppressing C. albicans proliferation, which concurrently curbs systemic inflammation and ceramide accumulation, thereby reducing cardiometabolic risk (Bao et al., 2023). Given that amphotericin B and fluconazole are broad-spectrum antifungal agents whose long-term use may incur significant side effects, whether antifungal therapy should be implemented as a potential clinical intervention for cardiometabolic diseases thus requires further clinical investigation and evidence-based validation. Second, targeted inhibition of microbial enzymatic activity is a promising therapeutic strategy. The groundbreaking discovery of microbial DPP4 isozymes has unveiled a novel mechanism (Wu et al., 2023). Consequently, developing specific inhibitors against fungal enzymes, such as C. parapsilosis lipase, can attenuate excessive FFA production, thereby ameliorating oxidative lipotoxicity and hepatic steatosis (Sun et al., 2021); this has significant therapeutic implications for CMD amelioration. ‌Furthermore, the depletion of fungal-derived metabolites (endogenous ethanol or ceramides) confers distinct physiological benefits. Notably, ceramides, designated as the ‘putative second cholesterol’ (Zhang et al., 2025), render pharmacological modulation of their biosynthetic pathways, such as serine palmitoyltransferase (SPT), a novel therapeutic paradigm for CMD management. Consequently, Myriocin (thermozymocidin), a potent SPT inhibitor, demonstrates substantial translational promise for mitigating CMDs (Gengatharan et al., 2025).

‌As previously indicated, fungal β-glucan, a prototypical pathogen-associated molecular pattern, serves as a master regulator of host immunity. Its binding to Dectin-1 receptors on immune cells primarily instigates inflammatory cascades (Liu et al., 2025). Pioneering studies have suggested β-glucan-specific nanobodies hold therapeutic promise owing to their target-blocking capacity (Liu et al., 2023). Developing Dectin-1 antagonists is a viable therapeutic alternative (Li et al., 2024) to mitigate inflammation-driven metabolic derangements. Moreover, dysbiosis within the gut mycobiome-bacteriome interactome fuels cardiometabolic pathogenesis via hub-mediated immuno-metabolic axes. ‌Accumulating clinical evidence supports the therapeutic efficacy of fungal-targeted transplantation or supplementation with probiotic fungi. Nevertheless, cutting-edge findings suggest that dietary modulation is the linchpin for reconfiguring gut microbiota, surpassing conventional microbiota transfer (Kennedy et al., 2025). Established paradigms, including Mediterranean, low-carbohydrate, and high-fiber diets, demonstrate a documented potential to correct metabolic derangements (Gao et al., 2024). Additionally, natural compounds constitute an indispensable therapeutic arsenal against CMD. Previous studies have demonstrated that Litchi chinensis seed (Xiang et al., 2022), echinacoside (Fan et al., 2025), Coptidis Rhizoma (Yang et al., 2022), and paeonol (Wu et al., 2020) exhibit dual lipid-glycemic modulatory efficacy, recalibrating fungal-bacterial interactomes to remodel gut ecological architectures. Furthermore, the indisputably beneficial role of exercise serves as a vital adjunct strategy for weight management (Jung et al., 2015), mitigation of metabolic dysregulation (Wewege et al., 2018), and cardiovascular health enhancement (Yue et al., 2022; Ramos et al., 2015). Contemporary research reveals that compared to sedentary counterparts, a 12-week regimen of high-intensity interval training significantly augmented the abundance of gut mycobiota including Verticillium, Ceratocystis, and Sarocladium. This elevation in fungal populations demonstrated significant correlation with exercise-induced improvements in key metabolic parameters—namely blood glucose levels, blood pressure, and lipid profiles (Wang et al., 2024).