Fungal microbiome and multiple sclerosis: The not-so-new kid on the block (2021)

Human hosts and commensal gut microbes have a symbiotic relationship, with hosts providing space and nutrients to microbes, and microbes supporting numerous physiological processes of the host, including digestion food, preventing pathogen colonization, and immune system modulation [[1]Lynch S.V. Pedersen O. The human intestinal microbiome in health and disease.N Engl J Med. 2016; 375: 2369-2379Crossref PubMed Scopus (1419) Google Scholar]. Thus, it is not surprising that perturbations in this homeostasis are linked with a number of diseases [[1]Lynch S.V. Pedersen O. The human intestinal microbiome in health and disease.N Engl J Med. 2016; 375: 2369-2379Crossref PubMed Scopus (1419) Google Scholar]. In last two decades non-culture-based sequencing techniques have afforded a better understanding of the human microbiome in health and disease, including multiple sclerosis (MS). Several groups, including ours, have shown that patients with MS have gut dysbiosis (specific bacteria either enriched or depleted) [[2]Freedman S.N. Shahi S.K. Mangalam A.K. The "gut feeling": breaking down the role of gut microbiome in multiple sclerosis.Neurotherapeutics. 2018; 15: 109-125Crossref PubMed Scopus (72) Google Scholar]. However, most studies have only analyzed bacteria even though the microbiome also consists of fungi and viruses. In this article, Shah et al. [[3]Saumya S. Alberto L. Yair D. et al.Alterations of the gut mycobiome in patients with MS.EBioMedicine. 2021; 71103557Summary Full Text Full Text PDF PubMed Scopus (8) Google Scholar] profile the fungal microbiome (mycobiome) in patients with MS (pwMS) and show that these patients have a distinct mycobiome compared to healthy control (HC) participants. Study by Shah et. al and another in preprint by Yadav et. al. showing fungal dysbiosis in pwMS [[4]Yadav M. Ali S. Shrode R.L. et al.Multiple sclerosis patients have an altered gut mycobiome and increased fungal to bacterial richness.bioRxiv. 2021; (2021.08.30)458212Google Scholar] begin to highlight the importance of the mycobiome in MS. Shat et al. compared the mycobiomes of 25 pwMS and 22 HCs and showed that the mycobiome of pwMS had higher fungal richness than that of HCs, with mycobiome composition remaining mostly stable over six-months [[3]Saumya S. Alberto L. Yair D. et al.Alterations of the gut mycobiome in patients with MS.EBioMedicine. 2021; 71103557Summary Full Text Full Text PDF PubMed Scopus (8) Google Scholar]. The mycobiome of pwMS was enriched for certain fungi such as Saccharomyces and Aspergillus. Interestingly, disease-modifying therapies, including dimethyl fumarate, which possesses anti-fungal properties, did not alter the mycobiome composition. The authors also associated mycobiome profiles with different microbiome compositions by classifying mycobiome profiles into two fungal clusters (i.e., mycotypes). Mycotype 1 was dominated by Saccharomyces, whereas Mycotype 2 had greater diversity with presence of Penicillium, Malassezia and Mucor besides Saccharomyces. There was a positive correlation between Saccharomyces and circulating basophil levels, and increased levels of effector memory CD4+ T cells in participants with the Mycotype 2 cluster. Collectively, these results demonstrate that the mycobiota is altered in the context of MS, which likely has implications on disease progression and severity, particularly considering a previous report showing a distinct mycobiome signature in patients with other diseases, such as inflammatory bowel disease, cancers, atherosclerosis, diabetes, obesity, and alcoholic liver disease [[5]Chin V.K. Yong V.C. Chong P.P. Amin Nordin S. Basir R. Abdullah M. Mycobiome in the gut: a multiperspective review.Mediators Inflamm. 2020; 20209560684Crossref PubMed Scopus (39) Google Scholar,[6]Gutierrez M.W. Arrieta M.C. The intestinal mycobiome as a determinant of host immune and metabolic health.Curr Opin Microbiol. 2021; 62: 8-13Crossref PubMed Scopus (6) Google Scholar]. Like bacteria, fungi are also proposed to play an important (symbiotic) role in maintaining immune homeostasis at mucosal surfaces by regulating both innate and adaptive immunity. Recognition of fungi through innate immune receptors such as Dectin-1, Dectin-2, c-type lectin receptors, and macrophage-inducible Ca2+-dependent lectin receptor help fine-tune immune responses in the gut [[6]Gutierrez M.W. Arrieta M.C. The intestinal mycobiome as a determinant of host immune and metabolic health.Curr Opin Microbiol. 2021; 62: 8-13Crossref PubMed Scopus (6) Google Scholar]. Additionally, fungi specifically Candida and Malassezia, are potent inducers of a systemic Th17 response and promote expansion of the neutrophil population [5Chin V.K. Yong V.C. Chong P.P. Amin Nordin S. Basir R. Abdullah M. Mycobiome in the gut: a multiperspective review.Mediators Inflamm. 2020; 20209560684Crossref PubMed Scopus (39) Google Scholar, 6Gutierrez M.W. Arrieta M.C. The intestinal mycobiome as a determinant of host immune and metabolic health.Curr Opin Microbiol. 2021; 62: 8-13Crossref PubMed Scopus (6) Google Scholar, 7Sparber F. Ruchti F. LeibundGut-Landmann S. Host immunity to malassezia in health and disease.Front Cell Infect Microbiol. 2020; 10: 198Crossref PubMed Scopus (18) Google Scholar]. The importance of the mycobiome for T cell activation and granulocytes expansion is highlighted by two recent studies that show the mycobiome was enriched in the offspring of wild mice that received embryos from laboratory mice or in laboratory mice that were reintroduced to the wild [[8]Rosshart S.P. Herz J. Vassallo B.G. et al.Laboratory mice born to wild mice have natural microbiota and model human immune responses.Science. 2019; 365Crossref PubMed Scopus (169) Google Scholar,[9]Yeung F. Chen Y.H. Lin J.D. et al.Altered immunity of laboratory mice in the natural environment is associated with fungal colonization.Cell Host Microbe. 2020; 27 (e6): 809-822Summary Full Text Full Text PDF PubMed Scopus (57) Google Scholar]. Laboratory mice differ from human immune system as they have reduced numbers of activated T cells and polymorphonuclear lymphocytes in their blood and these studies suggest that lack of complex commensal fungi in mice might be responsible for these differences in immune parameters. The study discussed here is limited by its small sample size, classification of fungi at low resolution, and the absence of a validation cohort of patients. As Candida and Saccharomyces are two of the most abundant fungi in the human mycobiome, the significantly reduced abundance of Candida observed here [[3]Saumya S. Alberto L. Yair D. et al.Alterations of the gut mycobiome in patients with MS.EBioMedicine. 2021; 71103557Summary Full Text Full Text PDF PubMed Scopus (8) Google Scholar] is surprising. Several human studies have shown relatively higher abundance of Candida both in healthy participants [[10]Nash A.K. Auchtung T.A. Wong M.C. et al.The gut mycobiome of the human microbiome project healthy cohort.Microbiome. 2017; 5: 153Crossref PubMed Scopus (318) Google Scholar] and in patients with disease, such as inflammatory bowel disease, atherosclerosis and type 2 diabetes mellitus [[5]Chin V.K. Yong V.C. Chong P.P. Amin Nordin S. Basir R. Abdullah M. Mycobiome in the gut: a multiperspective review.Mediators Inflamm. 2020; 20209560684Crossref PubMed Scopus (39) Google Scholar,[6]Gutierrez M.W. Arrieta M.C. The intestinal mycobiome as a determinant of host immune and metabolic health.Curr Opin Microbiol. 2021; 62: 8-13Crossref PubMed Scopus (6) Google Scholar]. We have also observed higher Candida levels in pwMS compared to HC using marker-based fungal classification [[4]Yadav M. Ali S. Shrode R.L. et al.Multiple sclerosis patients have an altered gut mycobiome and increased fungal to bacterial richness.bioRxiv. 2021; (2021.08.30)458212Google Scholar]. Lower Candida levels in the current study may be due to the geographic location, lifestyles, or dietary habits of the participants, or the bioinformatics pipeline used. Further, Saccharomyces has been associated with both a healthy mycobiome and certain diseases, suggesting either a strain-specific role of Saccharomyces in promoting disease, or that the overall composition of the mycobiome, and the bacterial microbiome, affects its disease-protective or promoting properties. Correlating the abundance of Saccharomyces and Candida with other components of the microbiome in the context of MS will be an important next step in beginning to uncover how fungi might protect or promotes disease. In conclusion, this study provides first evidence that the fungal component of the microbiome is disrupted in pwMS. This paves the way for future work characterizing the mycobiome in the context of disease using shotgun metagenomic sequencing and larger sample sizes, which, combined with mechanistic studies, will help in understanding the precise role of fungi in the pathobiology of MS. This commentary was written solely by AKM. The author declares no conflicts of interest. Alterations of the gut mycobiome in patients with MSThere is an alteration of the gut mycobiome in pwMS, compared to healthy controls. Further study is required to assess any causal association of the mycobiome with MS and its direct or indirect interactions with bacteria and autoimmunity. Full-Text PDF Open Access