PLMI Blog

The gut microbiome is a complex, multi-kingdom ecosystem composed of bacteria, viruses, archaea, and fungi. Emerging findings reveal the pivotal role of fungal communities, collectively referred to as the mycobiome, in modulating host physiology and immunity. While fungi comprise only 0.01%- 0.1% of the gut microbiome, their size, diverse metabolic functions, and immunomodulatory properties allow them to exert a significant influence on health, while helping to mitigate disease (1-2).

Dysbiosis, an imbalance and disruption in the fungal community, can contribute to a wide spectrum of pathologies, including autoimmune, metabolic, neuroinflammatory, and psychiatric conditions, underscoring the impact of fungi on the collective gut ecosystem and overall health.

Composition & Symbiosis of the Gut Mycobiome

The gut mycobiome—comprising the fungal community’s composition, genes, and metabolites—represents a vital component of the gut microbiota. The GI tract harbors a diverse and complex fungal ecosystem, with at least 66 genera and approximately 180 species (2). The predominant fungal phyla in the gut are Ascomycota and Basidiomycota, with notable genera including Saccharomyces, Candida, Malassezia, Cyberlindnera, Penicillium, Cladosporium, and Aspergillus. Among these, Candida albicans and Saccharomyces cerevisiae are particularly abundant and play significant roles in host-microbe interactions.

Fungal populations, typically reaching 1,000 cells per gram or milliliter of gut content, vary across anatomical sites due to distinct ecological conditions along the GI tract (3). Fungi colonize the gut, as well as the lungs and skin. The gut mycobiome interacts closely with microbiota and the immune system, having profound and robust roles in immune development, mucosal barrier function, and immune regulation.

Fungal cells are nearly ten times wider and one hundred times more voluminous than bacterial cells, enabling them with a unique capacity for interaction with host tissues. Fungi possess larger, more complex genomes with considerable variability in their genetic makeup. This genetic diversity supports a broad range of metabolic pathways and morphological adaptations, allowing fungi to perform various imperative functions, such as interacting with immune cells and modulating host immune responses.

The gut mycobiome interacts symbiotically with the gut microbiome to ensure homeostasis with the collective ecosystem and overall health.

The Immune-Mediated Role of the Mycobiome

The gut mycobiome plays a dynamic role in immune modulation, initiating interactions early in life and continuing throughout adulthood. Through complex engagement with epithelial cells, innate immune receptors, and antigen-presenting cells, fungi support mucosal tolerance and immune regulation.

Colonization of the gastrointestinal tract by commensals such as Candida albicans promotes immune maturation by driving the differentiation of T helper and innate lymphoid cells via pathways, such as Th17 activation. This leads to the release of cytokines (IL-17, IL-22) that reinforce epithelial integrity, recruit neutrophils, and bolster antimicrobial defenses. However, dysregulated Th17 responses are implicated in autoimmune diseases such as inflammatory bowel disease (IBD), underscoring the delicate immunological balance that fungi help maintain (4).

Fungal antigens also influence humoral immunity. Candida stimulates B-cell activation and class switching, inducing secretory IgA (sIgA) production at mucosal surfaces. This response aids in immune exclusion, pathogen neutralization, and the preservation of tolerance by differentiating pathogens from commensals (5).

Innate responses are similarly shaped by fungal cell wall components—β-glucans and mannans—which are recognized by pattern recognition receptors such as Dectin-1 and Toll-like receptor 2 (TLR2). These interactions activate dendritic cells, macrophages, and inflammasomes (e.g., NLRP3), triggering cytokine release (IL-1β, IL-23), enhancing antigen presentation and T-cell priming, and supporting barrier integrity and immune surveillance (1, 6).

These findings highlight the mycobiome’s broad influence on both local and systemic immune processes; a balanced mycobiome is essential for immune homeostasis. Disruptions and imbalances in the mycobiome—through fungal overgrowth or reduced microbial diversity—can impede regulation, promote chronic inflammation, and contribute to immune-mediated disorders.

Fungal Dysbiosis & Autoimmunity

Clinical and metagenomic studies increasingly link fungal dysbiosis to chronic inflammation and autoimmunity. In the context of immune suppression or microbial imbalance, commensal fungi such as Candida albicans can adopt pathogenic traits, releasing pro-inflammatory mediators that contribute to disease progression (1, 7). This shift has been implicated in IBD, liver disease, rheumatoid arthritis (RA), and multiple sclerosis (MS) (1, 7).

In murine models, C. albicans exacerbates colitis through Dectin-1 and TLR2 signaling, promoting elevated cytokine levels (IL-6, TNF-α, IL-17) and skewing immune responses toward inflammation (1, 8). Persistent fungal antigen exposure may impair self-tolerance via molecular mimicry and bystander activation, promoting autoimmunity (9).

In Crohn’s disease, elevated anti-Saccharomyces cerevisiae antibodies (ASCA) and increased Candida abundance with reduced fungal diversity support a dysregulated antifungal immune response (6, 7). Fungal cell wall components, including β-glucans and mannans, trigger innate immune pathways via pattern recognition receptors, contributing to cytokine release and T-cell polarization. Chronic activation of these pathways may drive immune imbalance.

Beyond the gut, fungal translocation in conditions like non-alcoholic steatohepatitis (NASH) has been associated with hepatic inflammation and fibrosis, implicating the mycobiome in systemic immune regulation (10). Similar mechanisms have been proposed in lupus and multiple sclerosis, particularly in genetically susceptible individuals (11-12).

Fungi play a critical role in immune surveillance and homeostasis. C. albicans supports mucosal immunity by stimulating antifungal IgG production through CARD9⁺ CX3CR1⁺ macrophages and by promoting Th17 responses vital for mucosal defense (13-14). Collectively, these findings position the mycobiome as a key modulator of both mucosal and systemic immunity.

The Mycobiome & Metabolic Balance

In addition to its immunomodulatory functions, the gut mycobiome is increasingly recognized as a key player in metabolic homeostasis (15). Emerging evidence implicates fungal dysbiosis in the etiology and progression of major metabolic disorders, including obesity, insulin resistance, and non-alcoholic fatty liver disease (NAFLD) (16).

Alterations in fungal community structure—characterized by reduced alpha diversity and overrepresentation of opportunistic genera, including Candida and Penicillium, and a decline in commensal species, such as Saccharomyces cerevisiae—have been consistently observed in individuals with metabolic syndrome and obesity (17). These compositional shifts may contribute to pathogenesis through multiple mechanisms, including modulation of lipid metabolism, bile acid signaling, intestinal permeability, and systemic inflammation.

Fungal metabolites and structural components, such as β-glucans and mannans, can directly influence host metabolic signaling pathways and also modulate bacterial communities, influencing the broader metabolic landscape of the gut ecosystem. Interkingdom crosstalk between fungi and bacteria influences short-chain fatty acid production, endotoxin release, and pro-inflammatory signaling—factors involved in insulin sensitivity and adipose tissue inflammation. As our understanding deepens, integrating the mycobiome into metabolic research frameworks may be critical for developing more nuanced, comprehensive, evidence-based approaches to health.

The Mycobiome–Brain Axis: Fungal Dysbiosis, Neuroimmune & Neuropsychiatric Conditions

While the gut microbiome’s impact on systemic immunity and metabolism is well established, its role in brain function—particularly via neuroimmune pathways—is a growing area of active research. Recent findings expand this perspective beyond bacteria, positioning the gut mycobiome as a critical, yet understudied, contributor to neuropsychiatric health (18).

Fungi exert robust effects on host physiology via immunologic signaling, microbial interactions, and the microbiota–gut–brain axis bidirectional communication linking the GI tract and the CNS through neural, endocrine, and immune pathways (19). Perturbations in the gut mycobiome can influence this axis at multiple levels by altering microbial metabolite profiles (short-chain fatty acids, tryptophan derivatives), modifying neuroactive compound availability and triggering systemic immune responses that affect brain plasticity, mood regulation, and cognition. In fact, emerging findings highlight the role of the mycobiome-gut-brain axis in contributing to these conditions, as noted in The Journal of Microorganisms (20). These findings were also echoed in a 2025 review published in Frontiers in Cellular Neuroscience (15).

Disruptions in fungal community structure (fungal dysbiosis) have been increasingly associated with neurodevelopmental and neuropsychiatric disorders, including major depressive disorder, generalized anxiety disorder, schizophrenia, autism spectrum disorder, attention-deficit hyperactivity disorder (ADHD), and Alzheimer’s disease (21-22). These associations are especially pronounced during critical periods of brain development when the gut-brain axis is highly plastic and susceptible to microbial-derived signaling.

Fungal dysbiosis is suggested to influence brain function primarily through immune activation and increased intestinal permeability. Certain fungal species—particularly Candida albicans and Saccharomyces cerevisiae—can induce mucosal immune responses that include the release of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α). These cytokines may translocate across the blood-brain barrier, promoting microglial activation and neuroinflammation—hallmarks of various psychiatric and neurodegenerative disorders (14). Concurrently, fungal components contribute to the disruption of epithelial tight junctions, leading to increased gut permeability, further enabling microbial antigens and metabolites to access systemic circulation and impede central nervous system signaling.

The immune system serves as a critical intermediary in these processes. Commensal fungi can stimulate antifungal IgG production via CARD9+ CX3CR1+ macrophages, offering protective surveillance against both fungal and bacterial overgrowth (13). Additionally, Candida albicans have been demonstrated to elicit a Th17-dominant immune response, driving secretion of IL-17 and IL-22—cytokines involved in mucosal defense and inflammation (13-14). While these responses are essential for pathogen control, chronic or dysregulated Th17 activation has been implicated in neuroinflammatory states and autoimmune neuropsychiatric conditions, highlighting the fine line between protective immunity and pathology.

These findings highlight the underrecognized yet biologically influential role of gut fungi in neuroimmune and neuropsychiatric health via the mycobiome-gut-brain axis.

Fungi & the Mycobiome: A New Frontier in Precision Medicine

As the scientific lens widens beyond bacteria, the gut mycobiome is emerging as a pivotal player in health and disease. Fungi exert broad physiological influence across the immune, metabolic, and neuropsychiatric axes. Far from being passive inhabitants, fungal communities actively engage with host systems, producing bioactive metabolites, shaping immune responses, and modulating interkingdom microbial dynamics. Fungal dysbiosis is emerging as a contributing factor in the pathogenesis of complex chronic health conditions.

This evolving understanding is reframing the mycobiome as a novel therapeutic target within the broader context of personalized medicine. Interventions aimed at restoring fungal balance are gaining traction. When integrated with multi-omics analyses—including genomics, transcriptomics, metabolomics, and immunomics—these tools provide a systems-level perspective of host-microbiome interactions to support collective health.

Don’t miss our upcoming event, The Gut Mycobiome: A Central Figure in Health and Disease, taking place on June 10th from 5–7 PM PDT. Join leading experts Elroy Vojdani, MD, Aristo Vojdani, PhD, and Jeffrey Bland, PhD, as they further explore the emerging science of the gut mycobiome and its profound influence on immune regulation, systemic homeostasis, chronic disease, and microbiome-based therapies.

This webinar will offer compelling insights into the intersection of clinical practice and research. Reserve your spot for an engaging discussion that will expand your understanding of the mycobiome’s role in health and disease—and its potential to reshape the future of medicine.

References

1. Huang H, Wang Q, Yang Y, Zhong W, He F, Li J. The mycobiome as integral part of the gut microbiome: crucial role of symbiotic fungi in health and disease. Gut Microbes. 2024 Jan-Dec;16(1):2440111. doi: 10.1080/19490976.2024.2440111. Epub 2024 Dec 15. PMID: 39676474; PMCID: PMC11651280.
2. Raimondi S, et al. (2019). Longitudinal Survey of Fungi in the Human Gut: ITS Profiling, Phenotyping, and Colonization. Front Microbiol, 10:1575. https://doi.org/10.3389/fmicb.2019.01575
3. Schulze J, Sonnenborn U. Yeasts in the gut: from commensals to infectious agents. Deutsches Arzteblatt Int. 2009;106(51–52):837–842. [DOI] [PMC free article] [PubMed] [Google Scholar]
4. Underhill DM, Iliev ID. The mycobiota: interactions between commensal fungi and the host immune system. Nat Rev Immunol. 2014 Jun;14(6):405-16. doi: 10.1038/nri3684. PMID: 24854590; PMCID: PMC4332855.
5. Kubinak, J., Round, J. Do antibodies select a healthy microbiota?. Nat Rev Immunol 16, 767–774 (2016). https://doi.org/10.1038/nri.2016.114
6. Gutierrez MW, Arrieta MC. (2021). The intestinal mycobiome as a determinant of host immune and metabolic health. Curr Opin Microbiol, 62:8–13. https://doi.org/10.1016/j.mib.2021.04.004
7. Sokol H, Leducq V, Aschard H, Pham HP, Jegou S, Landman C, Cohen D, Liguori G, Bourrier A, Nion-Larmurier I, Cosnes J, Seksik P, Langella P, Skurnik D, Richard ML, Beaugerie L. Fungal microbiota dysbiosis in IBD. Gut. 2017 Jun;66(6):1039-1048. doi: 10.1136/gutjnl-2015-310746. Epub 2016 Feb 3. PMID: 26843508; PMCID: PMC5532459.
8. Leonardi, I., Gao, I. H., Lin, W.-Y., Allen, M., Li, X. V., Fiers, W. D., Bialt De Celie, M., Putzel, G. G., Yantiss, R. K., Johncilla, M., Colak, D., & Iliev, I. D. (2022). Mucosal fungi promote gut barrier function and social behavior via Type 17 immunity. Cell, 185(5), 831–846.e14. https://doi.org/10.1016/j.cell.2022.01.027
9. Iliev ID, Leonardi I. Fungal dysbiosis: immunity and interactions at mucosal barriers. Nat Rev Immunol. 2017 Oct;17(10):635-646. doi: 10.1038/nri.2017.55. Epub 2017 Jun 12. PMID: 28604735; PMCID: PMC5724762.
10. Zhang, Fen et al. (2022). The gut mycobiome in health, disease, and clinical applications in association with the gut bacterial microbiome assembly
    The Lancet Microbe, Volume 3, Issue 12, e969 – e983
11. Geddes-McAlister J. Systems Biology in Fungal Research. J Fungi (Basel). 2022 May 4;8(5):478. doi: 10.3390/jof8050478. PMID: 35628734; PMCID: PMC9142880.
12. Geddes-McAlister J, Shapiro RS. New pathogens, new tricks: emerging, drug-resistant fungal pathogens and future prospects for antifungal therapeutics. Ann N Y Acad Sci. 2019 Jan;1435(1):57-78. doi: 10.1111/nyas.13739. Epub 2018 May 15. PMID: 29762860.
13. Doron I, Leonardi I, Li F XV, Semon WD, A B-D, Gao M, Migaud M, Lin IH, Wy KT, Kusakabe T, et al. Human gut mycobiota tune immunity via CARD9-dependent induction of anti-fungal IgG antibodies. 2021;184(4):1017–1031.e1014. 10.1016/j.cell.2021.01.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
14. Bacher P, Hohnstein T, Beerbaum E, Röcker M, Blango MG, Kaufmann S, Röhmel J, Eschenhagen P, Grehn C, Seidel K, et al. Human anti-fungal Th17 immunity and pathology rely on cross-reactivity against Candida albicans. 2019;176(6):1340–1355.e1315. 10.1016/j.cell.2019.01.041. [DOI] [PubMed] [Google Scholar]
15. Hadrich I, Turki M, Chaari I, Abdelmoula B, Gargouri R, Khemakhem N, Elatoui D, Abid F, Kammoun S, Rekik M, Aloulou S, Sehli M, Mrad AB, Neji S, Feiguin FM, Aloulou J, Abdelmoula NB, Sellami H. Gut mycobiome and neuropsychiatric disorders: insights and therapeutic potential. Front Cell Neurosci. 2025 Jan 8;18:1495224. doi: 10.3389/fncel.2024.1495224. PMID: 39845646; PMCID: PMC11750820.
16. Gutierrez, M. W., & Arrieta, M.-C. (2021). The intestinal mycobiome as a determinant of host immune and metabolic health. Current Opinion in Microbiology, 62, 8–13. https://doi.org/10.1016/j.mib.2021.04.004
17. Mar Rodríguez M, Pérez D, Javier Chaves F, Esteve E, Marin-Garcia P, Xifra G, Vendrell J, Jové M, Pamplona R, Ricart W, et al. Obesity changes the human gut mycobiome. Sci Rep. 2015;5(1). doi: 10.1038/srep14600.
18. D’Argenio V., Veneruso I., Gong C., Cecarini V., Bonfili L., Eleuteri A. M. (2022). Gut microbiome and mycobiome alterations in an in vivo model of Alzheimer’s disease. Genes (Basel) 13:1564. 10.3390/genes13091564 [DOI] [PMC free article] [PubMed] [Google Scholar
19. Chin V. K., Yong V. C., Chong P. P., Amin Nordin S., Basir R., Abdullah M. (2020). Mycobiome in the gut: A multiperspective review. Mediators Inflamm. 2020:9560684. 10.1155/2020/9560684 [DOI] [PMC free article] [PubMed] [Google Scholar]
20. Enaud R, Vandenborght LE, Coron N, Bazin T, Prevel R, Schaeverbeke T, Berger P, Fayon M, Lamireau T, Delhaes L. The Mycobiome: A Neglected Component in the Microbiota-Gut-Brain Axis. Microorganisms. 2018 Mar 9;6(1):22. doi: 10.3390/microorganisms6010022. PMID: 29522426; PMCID: PMC5874636.
21. Ahmed G. K., Ramadan H. K.-A., Elbeh K., Haridy N. A. (2024). Bridging the gap: Associations between gut microbiota and psychiatric disorders. Middle East Curr. Psychiatry 31:2. 10.1186/s43045-024-00395-9 [DOI] [Google Scholar]
22. Jones, L., Kumar, J., Mistry, A., Sankar Chittoor Mana, T., Perry, G., Reddy, V. P., et al. (2019). The transformative possibilities of the microbiota and mycobiota for health, disease, aging, and technological innovation. Biomedicines 7:24. doi: 10.3390/biomedicines7020024