Imbalance in gut fungi and immune problems in Chinese schizophrenia patients with metabolic syndrome

Schizophrenia (SZ) is a severe neuropsychiatric disorder characterized by cognitive impairment and a reduced life expectancy of 15–20 years, attributable in part to its frequent comorbidity with metabolic syndrome (MetS) (1, 2). Approximately one-third of SZ patients develop MetS (3), creating a vicious cycle that exacerbates psychiatric symptoms, accelerates cognitive decline, and increases cardiovascular mortality (4 –6). While antipsychotic side effects and lifestyle factors contribute to this comorbidity (7), emerging evidence implicates gut microbiome dysbiosis as a potential unifying mechanism bridging metabolic and neuropsychiatric pathology. Extensive research has characterized bacterial dysbiosis in both SZ and MetS separately, revealing altered microbial diversity, short-chain fatty acid production, and gut barrier integrity (8 –14). Our previous work demonstrated distinct fecal bacterial profiles in SZ-MetS patients correlating with immune dysfunction (12). However, the fungal microbiome (mycobiota) - an equally important component of the gut ecosystem - remains virtually unexplored in SZ-MetS comorbidity, despite its known roles in immune modulation and metabolic regulation (15 –17).

Fungal-bacterial interactions critically maintain gut homeostasis, with mycobiota dysbiosis implicated in inflammatory diseases and metabolic disorders (18 –20). Notably, Candida albicans overgrowth associates with obesity and insulin resistance (21), while Saccharomyces species modulate host immunity in ways relevant to neuroinflammation (22). The unique ability of fungi to form biofilms and penetrate intestinal barriers may make them particularly potent modulators of the gut-brain axis (23). Nevertheless, no studies to date have investigated gut mycobiota alterations in the SZ-MetS overlap, representing a critical knowledge gap given the established links between fungal dysbiosis, systemic inflammation, and neuropsychiatric conditions.

This study represents the first comprehensive analysis of gut fungal communities in Chinese SZ patients with MetS. We enrolled hospitalized SZ-MetS patients and age- and gender-matched healthy controls from Quzhou, China. Using internal transcribed spacer 1 (ITS1) sequencing and multi-parameter immunoassays, we characterize mycobiota profiles distinguishing SZ-MetS patients from matched controls; and examine correlations between fungal taxa and peripheral immune markers. Our findings may reveal novel mycobiota signatures contributing to the SZ-MetS vicious cycle, potentially informing future microbiome-targeted interventions for this high-risk population.

The intricate bidirectional relationship between SZ and MetS presents significant clinical challenges, where antipsychotic medications-while crucial for managing psychiatric symptoms - paradoxically contribute to metabolic dysregulation through mechanisms that go beyond their direct pharmacological effects (26, 27). Mounting evidence highlights the gut microbiota as a key mediator in this metabolic-neuropsychiatric crosstalk. Cutting-edge multi-omics research demonstrates that gut microbial imbalances often precede and may drive metabolic abnormalities in SZ patients, regardless of antipsychotic use (12, 28). Often referred to as the "second brain" and "metabolic organ", the gut microbiota serves as a vital link between nutritional metabolism and neurobehavioral regulation (29). Comprising both bacterial and fungal components, it regulates host metabolism through multiple pathways including short-chain fatty acids (SCFAs) production, maintenance of gut barrier function, and immune system regulation (9, 30, 31). Current understanding has been predominantly shaped by bacterial research, overlooking the potentially crucial contributions of fungal communities (12, 32). The gut mycobiota represents a distinct ecological niche that interacts with host physiology through mechanisms fundamentally different from those of bacteria. Unlike bacterial signaling which primarily occurs through SCFAs production, fungal communities influence host metabolism and immunity through unique pathways via β-glucan recognition by Dectin-1 receptors that modulates both innate and adaptive immune responses (33), production of neuroactive tryptophan metabolites that can cross the blood-brain barrier (34), and direct vagus nerve stimulation capable of altering central nervous system activity (35, 36). These fungal-specific mechanisms may be particularly relevant to SZ-MetS pathogenesis given the established roles of immune activation and neurotransmitter dysregulation in both SZ and MetS. Furthermore, the ability of certain fungal species to form biofilms and penetrate intestinal barriers positions them as potential amplifiers of gut-derived inflammation - a hypothesized contributor to both neuropsychiatric symptoms and metabolic dysfunction. Despite these plausible mechanistic links, the gut mycobiota remains conspicuously understudied in the context of SZ-MetS comorbidity, representing a critical gap in our understanding of how microbial communities influence the gut-brain-metabolism axis. This knowledge deficit persists even as research continues to elucidate bacterial dysbiosis patterns in SZ-MetS, including the depletion of anti-inflammatory butyrate producers and expansion of pro-inflammatory taxa (13, 28, 37, 38). The current study addresses this gap by providing the first systematic investigation of gut mycobiota alterations in SZ-MetS, offering new insights into how fungal communities may contribute to this complex comorbidity through their unique biological properties and host interaction mechanisms.

Our study pioneers the exploration of gut mycobiota in SZ-MetS patients, revealing profound taxonomic alterations despite comparable global α- and β-diversity. Taxonomic profiling uncovered striking shifts in specific fungal taxa, with SZ-MetS patients exhibiting enrichment of Candida, Trichosporon, and Issatchenkia alongside reduction of protective species like S. cerevisiae and P. ostreatus—findings that align with emerging literature on fungal dysbiosis in metabolic and neuroinflammatory disorders. For instance, C. albicans overgrowth, a prevalent species within the Candida genus, has been mechanistically linked to insulin resistance in MetS by disrupting gut mucosal barriers, increasing permeability, and promoting endotoxemia that impairs insulin signaling in peripheral tissues (39, 40). Concurrently, the depletion of S. cerevisiae—a known modulator of tight-junction proteins—may exacerbate gut leakage (41), while its reduction also disrupts SCFAs production critical for metabolic homeostasis (42, 43). Preclinical models demonstrate that S. cerevisiae-depleted mycobiomes correlate with reduced SCFAs levels, dyslipidemia, and altered energy metabolism, mirroring metabolic derangements in SZ-MetS (44). Mechanistically, these fungal alterations may influence neuropsychiatric function through dual pathways: neurotransmitter regulation and immunomodulation. Altered fungi such as Trichosporon promote the release of pro-inflammatory cytokines that disrupt neural plasticity, while S. cerevisiae depletion may reduce production of neuroactive metabolites like serotonin and GABA (45 –47). In animal models, Saccharomyces boulardii supplementation restores brain serotonin levels and alleviates neuropsychiatric-like behaviors, underscoring fungi's direct impact on the gut-brain axis (48). Additionally, fungal dysbiosis triggers abnormal immune activation in SZ-MetS, with Trichosporon-induced pro-inflammatory responses affecting neural transmission and synaptic function (20, 49). Recent research has also shown that fungi-induced changes in gut-associated lymphoid tissue further amplify immune-neuroendocrine crosstalk (50), emphasizing the complex interaction between gut mycobiota, immunity, and neuropsychiatric dysfunction in this comorbid population. Notably, a six-species fungal signature (S. cerevisiae, T. asahii, C. albicans, P. ostreatus, Lodderomyces elongisporus, Wickerhamomyces anomalus) exhibited exceptional diagnostic accuracy (AUC = 0.86), underscoring the unique utility of mycobiota profiling for identifying disease-specific microbial signatures. This performance aligns with a previous study by Xing et al., in which a decision tree-based model of five bacterial taxa achieved an AUC of 0.94 for discriminating SZ patients with and without MetS (8). Collectively, these findings highlight the diagnostic potential of gut microbiota—encompassing both bacterial and fungal communities—for SZ-MetS. Future research should prioritize validation of these mycobiota signatures in independent multicenter cohorts to facilitate their translation into clinical practice.

Our findings demonstrate significant species-specific interactions between gut mycobiota and host physiology in SZ-MetS patients, building upon and extending previous research in this field (19, 20). Most notably, we observed a strong positive correlation between T. asahii abundance and pro-inflammatory chemokines, particularly MIP-1α. This association aligns with established mechanisms of fungal pathogenicity, as T. asahii cell wall β-glucans are known to activate Dectin-1 receptors on macrophages, triggering NLRP3 inflammasome assembly and subsequent release of IL-1β and MIP-1α (33, 51). These inflammatory mediators may contribute to both the metabolic and neuropsychiatric components of SZ-MetS by promoting insulin resistance and neuroinflammation. Conversely, we found that reduced levels of S. cerevisiae were significantly associated with elevated IL-1β and MIP-1α. This inverse relationship supports the emerging understanding of S. cerevisiae as an immunomodulatory commensal, capable of attenuating TLR-mediated inflammatory responses through multiple mechanisms, including upregulation of regulatory cytokines and stabilization of gut barrier function (52). The protective effects of S. cerevisiae may be particularly relevant in SZ-MetS, where chronic low-grade inflammation is a hallmark feature. From a metabolic perspective, our data reveal complex fungal-host interactions. L. elongisporus showed a strong positive correlation with serum triglyceride levels, consistent with animal studies demonstrating its capacity to enhance hepatic lipid synthesis via PPAR-γ activation (53). Conversely, C. albicans abundance was inversely related to triglyceride levels, mirroring observations in NASH patients where C. albicans may compete for lipid nutrients (54). The immunological implications of mycobiota alterations were further underscored by our finding that W. muriae depletion correlated with elevated IL-8. This rare basidiomycete has been shown to promote regulatory T cell differentiation in the intestinal mucosa (55), suggesting its reduction in SZ-MetS may contribute to the disruption of immune homeostasis. Collectively, these observations support a model wherein gut mycobiota dysbiosis participates in a vicious cycle of SZ-MetS pathophysiology: fungal-driven inflammation exacerbates metabolic dysfunction, while resulting metabolic disturbances (e.g., hypertriglyceridemia) create an environment favoring further fungal dysbiosis (56). This cycle may be amplified by virulence factors such as fungal phospholipases, which directly damage host tissues and potentiate inflammatory responses (57). Our findings thus position the gut mycobiota as both a contributor to and consequence of SZ-MetS pathology, offering multiple potential intervention targets.

Building on the taxonomic and functional shifts in the gut mycobiota described above, integrating these findings with our prior characterization of gut bacterial communities in SZ-MetS patients provides a more holistic perspective on microbial dysbiosis in this comorbidity (12). Our prior work identified significant bacterial perturbations, including depletion of anti-inflammatory taxa such as Bacteroides and Faecalibacterium alongside enrichment of pro-inflammatory genera like Escherichia-Shigella and Klebsiella. These bacterial shifts are likely to interact with the fungal dysbiosis characterized in the current study, as bacterial and fungal communities in the gut maintain intricate reciprocal relationships that regulate ecosystem stability (15, 18). Mechanistically, bacterial metabolites such as SCFAs, whose production is compromised in SZ-MetS due to reduced SCFA-producing bacteria (12), play a role in constraining fungal overgrowth by modulating gut pH and reinforcing intestinal barrier integrity (30, 42). The depletion of S. cerevisiae observed in our current study— a species known to synergize with SCFA-producing bacteria to stabilize mucosal barriers—may thus be exacerbated by the concurrent loss of bacterial SCFA sources. Conversely, the enrichment of opportunistic fungi like C. albicans and T. asahii in SZ-MetS could disrupt bacterial homeostasis: these fungi secrete phospholipases and proteases that degrade intestinal barriers (57), creating a permissive environment for pro-inflammatory bacteria to translocate and amplify systemic inflammation. Notably, both bacterial and fungal dysbiosis in SZ-MetS correlate with elevated pro-inflammatory cytokines (e.g., IL-6, MIP-1α), suggesting a convergent impact on immune activation. For instance, bacterial lipopolysaccharides and fungal β-glucans may synergistically activate TLR4 and Dectin-1 signaling pathways (33, 51), driving the chronic low-grade inflammation that links metabolic dysfunction and neuropsychiatric symptoms. Such cross-kingdom interactions likely contribute to the "vicious cycle" of gut barrier impairment, immune dysregulation, and clinical manifestations in SZ-MetS, highlighting the need to consider multi-kingdom microbial dynamics in future mechanistic investigations. While these observations support potential bacterial-fungal crosstalk in SZ-MetS, the current study did not explicitly investigate the direct molecular or ecological mechanisms underlying such interactions. This represents an important avenue for future research, as disentangling these relationships could reveal novel therapeutic targets that simultaneously modulate both microbial kingdoms.

While our findings provide important insights, several limitations must be acknowledged. First, the cross-sectional design precludes establishing causal relationships between mycobiota alterations and disease progression. Second, while we controlled for major confounders, the potential effects of antipsychotic medications on fungal communities require dedicated investigation through medication-naïve studies. Third, our single-center design and specific ethnic composition may limit the generalizability of findings to other populations. Fourth, the diagnostic value of key functional fungal taxa identified in this study is solely based on results from the discovery cohort, with no independent validation cohort to confirm their reliability and robustness, which hinders the direct translation of these findings into clinical applications. Finally, the functional consequences of observed mycobiota changes warrant verification through mechanistic studies employing gnotobiotic models or multi-omics approaches.

This study comprehensively characterizes gut mycobiota dysbiosis in Chinese SZ-MetS patients, revealing distinct taxonomic shifts including enrichment of Candida, Trichosporon, and Issatchenkia, alongside reduction of protective taxa like S. cerevisiae and P. ostreatus. Despite comparable global diversity, these compositional changes correlate with systemic immune dysfunction, as evidenced by elevated pro-inflammatory cytokines and species-specific associations with metabolic/clinical parameters. A six-species fungal signature demonstrates robust diagnostic accuracy, highlighting mycobiota's potential as novel biomarkers for SZ-MetS. Collectively, these findings establish gut mycobiota dysbiosis as a critical contributor to the SZ-MetS vicious cycle. Future research should prioritize longitudinal studies to track mycobiota dynamics during disease progression, mechanistic investigations using gnotobiotic models to clarify fungal-mediated immune-metabolic crosstalk, and clinical trials evaluating S. cerevisiae-based probiotics to restore gut homeostasis. Additionally, integrating metatranscriptomic and metabolomic approaches to explore fungal-bacterial interactions may unveil innovative therapeutic targets for this complex comorbidity.