Schizophrenia (SCZ) is a chronic and severe mental disorder characterized by relapsing episodes, prolonged course, and residual symptoms. Symptoms of SCZ fall into three main categories: psychotic, negative, and cognitive. Psychotic symptoms include hallucinations—sensory experiences such as seeing, hearing, or feeling things that are not present—and delusions, involving strong, often irrational beliefs. Negative symptoms encompass reduced motivation, diminished interest in daily activities, social withdrawal, and challenges in emotional expression and daily functioning. Cognitive symptoms typically include difficulties with attention, concentration, and memory.

Prior studies have increasingly focused on the microbiome–gut–brain axis, a complex communication system linking the gastrointestinal (GI) tract to the brain, in relation to SCZ (Ju et al., 2023). While considerable attention has been directed at the bacterial components of the gut microbiota in SCZ, the fungal aspect, or mycobiome, remains less explored. Nonetheless, emerging evidence suggests a potential link between gut mycobiome dysbiosis and SCZ development.

Yuan et al. (2024) conducted an analysis of gut mycobiota in 109 chronic SCZ patients and 77 controls, identifying significant reductions in fungal diversity and an overrepresentation of Candida species linked to inflammatory processes. This study used ITS sequencing to profile fungal diversity. They observed significant alterations in the mycobiota composition in SCZ patients, marked by a reduced diversity of fungal species compared to healthy controls. This dysbiosis was characterized by a depletion of fungi, such as Saccharomyces cerevisiae, known for its immune-modulatory effects, potentially impacting gut homeostasis and immune regulation in these patients. On the other hand, Candida albicans, an opportunistic fungal species commonly found in the human GI tract, plays a central role in this fungal dysbiosis. The overgrowth of Candida albicans has been linked to chronic inflammatory states and increased gut permeability, promoting neuroinflammatory responses through the production of pro-inflammatory molecules such as β-glucans (Huffnagle and Noverr, 2013; Huang et al., 2024; Kearns, 2024; Villavicencio-Tejo et al., 2023; Yuan et al., 2024). Yuan et al. (2024) demonstrated that a Candida-dominant enterotype correlates with more severe psychotic symptoms and heightened systemic inflammation. In another study, Yuan et al. (2023) investigated the combined effects of genetic risk and mycobiome dysbiosis on SCZ risk among 137 drug-naïve, first-episode SCZ patients and 76 healthy controls. Patients with a higher Polygenic Risk Score (PRS), a measure quantifying the cumulative genetic predisposition to SCZ, exhibited a Candida-dominant enterotype (Yuan et al., 2023). These findings highlight the interplay between genetic predispositions, fungal dysbiosis, and disease severity. For a summary of observed dysbiosis patterns and their clinical implications, see Table 2.

Further research by Yuan et al. (2022) explored changes in mycobiome composition and fungi-bacteria interaction networks in 205 SCZ patients compared to 125 healthy controls, using 18S ribosomal RNA gene sequencing. The study found reduced fungal α-diversity in SCZ patients, along with an altered fungi-to-bacteria diversity ratio. Notably, higher levels of Purpureocillium were associated with more severe psychiatric symptoms and poorer cognitive function in SCZ patients, emphasizing the potential impact of specific fungal species on disease progression (Yuan et al., 2022).

In an earlier study, Zhang et al. (2020) examined gut mycobiota dysbiosis in drug-naïve SCZ patients using ITS1-based DNA sequencing, comparing 10 SCZ patients to 16 healthy controls. The results revealed reduced fungal alpha diversity and altered composition, with higher levels of Chaetomium and lower levels of Trichoderma in SCZ patients. Additionally, SCZ patients exhibited an intensified bacteria-fungi interaction network, suggesting disrupted interkingdom interactions within the gut microbiome, which may play a role in SCZ pathophysiology (Zhang et al., 2020).

Given the observed overrepresentation of Candida albicans and its role in systemic inflammation, therapeutic strategies such as antifungal agents or probiotics targeting fungal dysbiosis could help restore gut homeostasis. Early evidence suggests that probiotics like Saccharomyces boulardii may reduce fungal overgrowth and improve gut barrier integrity, potentially mitigating neuroinflammatory pathways linked to SCZ (Kelesidis and Pothoulakis, 2012). These findings underscore the potential of therapeutic strategies targeting fungal dysbiosis, such as probiotics, to mitigate inflammation and improve gut-brain axis health in SCZ.

A detailed overview of SCZ-related findings, methodologies, and main fungal communities identified is provided in Tables 1, 2.

Alzheimer’s disease (AD) is a chronic neurodegenerative condition characterized by amyloid beta plaques, neurofibrillary tangles, and both central and systemic inflammation, primarily affecting the medial temporal lobe and associative neocortical regions. Recently, the gut microbiome has gained attention as a modifiable risk factor for AD due to its bidirectional communication with the brain. Dysbiosis of the gut microbiota has been associated with the initiation and progression of neuroinflammatory processes that underlie AD (Seo and Holtzman, 2024). Emerging research suggests that the fungal component of the gut microbiome, or mycobiome, may also play a significant role in AD pathology (Seo and Holtzman, 2024).

A study by D’Argenio et al. (2022) analyzed the mycobiome of 3xTg-AD mice, a widely used model for AD, revealing a notable increase in fungi from the Dipodascaceae family compared to wild-type mice. To analyze the fungal composition, D’Argenio et al. (2022) utilized ITS sequencing in their assessment of the mycobiome within AD mouse models, revealing significant fungal shifts related to AD pathology. This family has been linked to metabolic disruptions, as it is also elevated in obese individuals and correlates with adiposity and cholesterol levels (Mar Rodríguez et al., 2015). Given the metabolic dysregulation observed in AD, D’Argenio et al. (2022) hypothesized that Dipodascaceae overgrowth may contribute to AD’s metabolic profile. However, further studies are needed to confirm these findings and elucidate the specific mechanisms involved (D’Argenio et al., 2022).

Dietary adjustments have shown potential in modulating the gut microbiome, which could impact AD progression. Nagpal et al. (2020) conducted a study on older adults with mild cognitive impairment (MCI) who followed either a modified Mediterranean ketogenic diet (MMKD) or the American Heart Association Diet (AHAD) for 6 weeks. Mycobiome analysis through fungal rRNA ITS1 gene sequencing revealed that MCI patients had higher proportions of fungal families and genera, including Sclerotiniaceae, Phaffomycetaceae, and Botrytis, compared to cognitively normal (CN) individuals. Notably, the MMKD intervention had a more substantial impact on the mycobiome than the AHAD, particularly in reducing levels of Botrytis, which was elevated in MCI patients at baseline. Additionally, the MMKD intervention led to an increase in Geotrichum abundance and a reduction in Saccharomyces, Zygosaccharomyces, and Aureobasidium, changes that may contribute to an improved gut environment. This suggests that diet-based interventions could modulate the gut mycobiome in ways that may benefit cognitive health. The study also highlighted correlations between specific fungal genera and Alzheimer’s biomarkers in cerebrospinal fluid (CSF). For example, Aspergillus and Meyerozyma were negatively correlated with amyloid-beta 40 and positively with tau protein levels in both CN and MCI patients, while Wallemia showed a negative correlation with tau markers in MCI but not CN subjects. These fungal biomarkers could help stratify patients based on their mycobiome profiles, enabling personalized dietary or pharmacological interventions (Nagpal et al., 2020).

While biomarkers derived from the gut mycobiome offer insights into systemic changes, the detection of fungal species directly within AD brains highlights a more localized impact, further implicating fungal dysbiosis in AD pathology. Phuna and Madhavan detected Candida spp., Malassezia spp., Cladosporium spp., and Alternaria spp. in AD brains, suggesting that these fungi may inadvertently reach the brain, especially in immunocompromised individuals, through a compromised epithelial barrier (Phuna and Madhavan, 2022). Candida species, for instance, may induce fungal glial granulomas with accumulated amyloid precursor protein, while Malassezia species can activate neuroinflammatory Th1 and Th17 immune responses. The roles of Cladosporium and Alternaria in AD are less understood, but these fungi may contribute to neuroinflammation and could potentially be involved in acetylcholinesterase inhibition. The presence of these fungi may collectively drive chronic neuroinflammation and neurodegeneration in AD. Additionally, targeting specific fungal biomarkers could provide a novel approach for early diagnosis and monitoring of disease progression (Nagpal et al., 2020).

Overall, these studies underscore the complex relationship between the gut mycobiome and AD, highlighting potential avenues for therapeutic interventions. Diet-based strategies, particularly those resembling the Mediterranean ketogenic diet, may offer benefits by modulating mycobiome composition. Additionally, mycobiome biomarkers could serve as tools for monitoring AD progression and treatment efficacy. As research progresses, a deeper understanding of these fungal contributions could lead to targeted approaches that address both bacterial and fungal dysbiosis in AD.

Key findings on fungal dysbiosis in AD, including methodologies and clinical implications, are summarized in Tables 1, 2.

Autism Spectrum Disorders (ASD) are complex neurodevelopmental conditions characterized by repetitive behaviors, restricted interests, and significant challenges in communication and social interaction (CDC, 2024). Despite extensive research, the exact causes of ASD remain elusive, though it is widely accepted that both genetic and environmental factors contribute to its development.

Recent studies have underscored a strong link between gastrointestinal (GI) issues and the severity of ASD symptoms. Individuals with ASD frequently experience a higher prevalence of GI disturbances, prompting researchers to explore the gut-brain axis and its potential role in ASD pathophysiology (Adams et al., 2011; Wang et al., 2011). Specifically, the gut microbiota has become a focal point of interest. Emerging evidence suggests that gut dysbiosis may correlate with the severity of ASD symptoms. This dysbiosis often manifests as reduced bacterial diversity and a decrease in beneficial commensal bacteria (Hughes et al., 2018). The mycobiome, the fungal component of the microbiome, has also gained attention, despite being previously overlooked in gut-brain axis research (Iovene et al., 2017; Strati et al., 2017).

In ASD, the fungal families Saccharomycetaceae and Debaryomycetaceae have been observed at altered levels. Saccharomycetaceae, which includes common yeast species, may play a role in GI issues frequently reported in ASD, potentially through interactions that influence gut motility and permeability. The presence of Debaryomycetaceae may contribute to neurobehavioral symptoms by affecting microbial metabolites that impact neurodevelopmental pathways (Strati et al., 2017; Zou et al., 2021; Alharthi et al., 2022)?. These alterations suggest that fungal communities may play a role in the severity of ASD-related GI issues and behavioral symptoms. This study used next-generation sequencing (NGS) techniques to evaluate fungal diversity, identifying associations between specific fungal taxa, like Saccharomycetaceae, and autism symptom severity (Strati et al., 2017).

The role of Candida species in ASD appears limited compared to other taxa. In ASD, although no significant differences in overall Candida abundance were observed compared to typically developing children, Candida albicans exacerbated GI symptoms in some cases (Strati et al., 2017). Therefore, targeting the mycobiome could represent a promising therapeutic approach for alleviating GI symptoms in children with ASD, potentially reducing symptom severity and enhancing quality of life (Strati et al., 2017). For ASD, targeted therapies such as probiotics or carefully monitored antifungal agents could help alleviate symptoms. However, their application requires caution due to potential toxicity and antifungal resistance (Alookaran et al., 2022). Emerging research suggests that restoring fungal balance through diet or fecal microbiota transplantation (FMT) may also hold promise in improving ASD outcomes (Strati et al., 2017; Wang L.-J. et al., 2023). Developing improved research methodologies will be crucial to optimizing these treatments and ensuring their efficacy and safety in managing ASD symptoms (Lewandowska-Pietruszka et al., 2023). A summary of ASD-associated fungal species and their potential neurobehavioral impacts can be found in Table 2.

In a broader point of view, recent research has highlighted the complex interactions between the gut microbiota and mycobiota, suggesting that these interactions might contribute significantly to ASD symptom severity. For instance, imbalances between bacterial and fungal populations in the gut may affect host microRNA expression, which in turn could regulate bacterial growth and contribute to ASD development (Yap et al., 2021). Additionally, small non-coding RNAs (sncRNAs), including microRNAs (miRNAs) and piwi-interacting RNAs (piRNAs), have been detected in fecal samples from individuals with ASD, suggesting a potential mechanism by which gut dysbiosis could exacerbate ASD symptoms through transcriptional regulation and inflammatory processes (Chiappori et al., 2022). These findings suggest that targeting gut dysbiosis may indirectly modulate RNA-mediated inflammatory pathways, offering a novel avenue for therapeutic research.

Current studies reveal a connection between reduced fungal diversity and mood-related disorders, suggesting that specific fungal taxa may influence disease progression. However, the causal relationships between fungal dysbiosis and neuropsychiatric outcomes remain unclear. Additionally, the interplay between fungal and bacterial communities in shaping the gut-brain axis is underexplored, limiting our ability to fully understand the synergistic effects.

While biomarkers derived from the gut mycobiome show promise for early diagnosis and treatment monitoring, their clinical utility remains unproven. Longitudinal studies and multi-omic approaches are urgently needed to validate these findings and establish the mechanistic pathways underlying these associations.

Therapeutic strategies addressing fungal dysbiosis—such as probiotics, dietary interventions, or antifungal therapies—show promise in mitigating the impact of the gut mycobiome on neuropsychiatric disorders. These approaches, discussed in the specific sections, underscore the need for further clinical validation and personalized interventions. Incorporating the mycobiome as a biomarker, as highlighted in public health studies (Buytaers et al., 2024), could also pave the way for stratified therapies and better health monitoring in neuropsychiatric populations.

Advancing our understanding of the gut mycobiome in neuropsychiatric disorders will require comprehensive, interdisciplinary research. Multi-omic frameworks combining metagenomics, metabolomics, and transcriptomics should be prioritized to capture the complexity of fungal-bacterial interactions. Moreover, linking genetic predispositions, such as polygenic risk scores (PRS), with mycobiome data could enhance our understanding of disease susceptibility and progression. Finally, identifying reliable fungal biomarkers remains a critical objective for advancing diagnostic and therapeutic innovations in neuropsychiatry.