Abstract
In this study, we tested the feces of children with ASD and those of healthy children, and the overall changing of the gut fungal community was observed in ASD children compared with controls. However, there were no abundant fungi populations showed significant variations between the ASD and Control group both at phylum and class level. Among the 507 genera identified, Saccharomyces and Aspergillus showed significant differences between ASD (59.07%) and Control (40.36%), indicating that they may be involved in the abnormal gut fungal community structure of ASD. When analyzed at the species level, a decreased abundance in Aspergillus versicolor was observed while Saccharomyces cerevisiae was increased in children with ASD relative to controls. Overall, this study characterized the fungal microbiota profile of children with ASD and identified potential diagnostic species closely related to the immune response in ASD.
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Adams, J. B., Johansen, L. J., Powell, L. D., Quig, D., & Rubin, R. A. (2011). Gastrointestinal flora and gastrointestinal status in children with autism - comparisons to typical children and correlation with autism severity. BMC Gastroenterology, 11, 22. https://doi.org/10.1186/1471-230x-11-22.
Ahmad, S. F., Ansari, M. A., Nadeem, A., Bakheet, S. A., Al-Ayadhi, L. Y., Alotaibi, M. R., et al. (2019). Dysregulation of T cell immunoglobulin and mucin domain 3 (TIM-3) signaling in peripheral immune cells is associated with immune dysfunction in autistic children. Molecular Immunology, 106, 77–86. https://doi.org/10.1016/j.molimm.2018.12.020.
Andersen, L. O., Vedel Nielsen, H., & Stensvold, C. R. (2013). Waiting for the human intestinal Eukaryotome. ISME Journal, 7(7), 1253–1255. https://doi.org/10.1038/ismej.2013.21.
Baio, J., Wiggins, L., Christensen, D. L., Maenner, M. J., Daniels, J., Warren, Z., et al. (2018). Prevalence of autism spectrum disorder among children aged 8 years - Autism and developmental disabilities monitoring network, 11 sites, United States, 2014. MMWR Surveillance Summary, 67(6), 1–23. https://doi.org/10.15585/mmwr.ss6706a1.
Bell, C. C. (1994). DSM-IV: Diagnostic and statistical manual of mental disorders. Essentials of Pain Medicine, 272(10), 828–829.
Berding, K., & Donovan, S. M. (2018). Diet can impact microbiota composition in children with autism spectrum disorder. Frontiers in Neuroscience, 12, 515. https://doi.org/10.3389/fnins.2018.00515.
Bolyen, E., Rideout, J. R., Dillon, M. R., Bokulich, N. A., Abnet, C. C., Al-Ghalith, G. A., et al. (2019). Author correction: Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2. Nature Biotechnology, 37(9), 1091. https://doi.org/10.1038/s41587-019-0252-6.
Borre, Y. E., Moloney, R. D., Clarke, G., Dinan, T. G., & Cryan, J. F. (2014). The impact of microbiota on brain and behavior: Mechanisms & therapeutic potential. Advances in Experimental Medicine and Biology, 817, 373–403. https://doi.org/10.1007/978-1-4939-0897-4_17.
Burrus, C. J. (2012). A biochemical rationale for the interaction between gastrointestinal yeast and autism. Medical Hypotheses, 79(6), 784–785. https://doi.org/10.1016/j.mehy.2012.08.029.
Chen, R., Liu, D., Guo, P., & Lin, W. (2018). Varicuothiols A and B, new fungal metabolites from Aspergillus versicolor with anti-inflammatory activities. Chemistry & Biodiversity, 15(1), e1700445. https://doi.org/10.1002/cbdv.201700445.
Cheng, S. C., van de Veerdonk, F., Smeekens, S., Joosten, L. A., van der Meer, J. W., Kullberg, B. J., et al. (2010). Candida albicans dampens host defense by downregulating IL-17 production. The Journal of Immunology, 185(4), 2450–2457. https://doi.org/10.4049/jimmunol.1000756.
Collins, S. M., & Bercik, P. (2009). The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease. Gastroenterology, 136(6), 2003–2014. https://doi.org/10.1053/j.gastro.2009.01.075.
David, L. A., Maurice, C. F., Carmody, R. N., Gootenberg, D. B., Button, J. E., Wolfe, B. E., et al. (2014). Diet rapidly and reproducibly alters the human gut microbiome. Nature, 505(7484), 559–563. https://doi.org/10.1038/nature12820.
Finegold, S. M. (2011). Desulfovibrio species are potentially important in regressive autism. Medical Hypotheses, 77(2), 270–274. https://doi.org/10.1016/j.mehy.2011.04.032.
Finegold, S. M., Dowd, S. E., Gontcharova, V., Liu, C., Henley, K. E., Wolcott, R. D., et al. (2010). Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe, 16(4), 444–453. https://doi.org/10.1016/j.anaerobe.2010.06.008.
Gabriele, S., Sacco, R., & Persico, A. M. (2014). Blood serotonin levels in autism spectrum disorder: A systematic review and meta-analysis. European Neuropsychopharmacology, 24(6), 919–929. https://doi.org/10.1016/j.euroneuro.2014.02.004.
Hittinger, C. T. (2013). Saccharomyces diversity and evolution: A budding model genus. Trends in Genetics, 29(5), 309–317. https://doi.org/10.1016/j.tig.2013.01.002.
Hoffmann, C., Dollive, S., Grunberg, S., Chen, J., Li, H., Wu, G. D., et al. (2013). Archaea and fungi of the human gut microbiome: Correlations with diet and bacterial residents. PLoS ONE, 8(6), e66019. https://doi.org/10.1371/journal.pone.0066019.
Iovene, M. R., Bombace, F., Maresca, R., Sapone, A., Iardino, P., Picardi, A., et al. (2017). Intestinal dysbiosis and yeast isolation in stool of subjects with autism spectrum disorders. Mycopathologia, 182(3–4), 349–363. https://doi.org/10.1007/s11046-016-0068-6.
Kaluzna-Czaplinska, J., & Blaszczyk, S. (2012). The level of arabinitol in autistic children after probiotic therapy. Nutrition, 28(2), 124–126. https://doi.org/10.1016/j.nut.2011.08.002.
Kantarcioglu, A. S., Kiraz, N., & Aydin, A. (2016). Microbiota-gut-brain axis: Yeast species isolated from stool samples of children with suspected or diagnosed autism spectrum disorders and in vitro susceptibility against nystatin and fluconazole. Mycopathologia, 181(1–2), 1–7. https://doi.org/10.1007/s11046-015-9949-3.
Kidd, P. M. (2002). Autism, an extreme challenge to integrative medicine. Part 2: Medical management. Alternative Medicine Review, 7(6), 472–499.
Kim, Y. S., & Leventhal, B. L. (2015). Genetic epidemiology and insights into interactive genetic and environmental effects in autism spectrum disorders. Biological Psychiatry, 77(1), 66–74. https://doi.org/10.1016/j.biopsych.2014.11.001.
Kobliner, V., Mumper, E., & Baker, S. M. (2018). Reduction in obsessive compulsive disorder and self-injurious behavior with Saccharomyces boulardii in a child with autism: A case report. Integrative Medicine (Encinitas), 17(6), 38–41.
Kohler, J. R., Hube, B., Puccia, R., Casadevall, A., & Perfect, J. R. (2017). Fungi that infect humans. Microbiol Spectrum, 5(3), a019273. https://doi.org/10.1128/microbiolspec.FUNK-0014-2016.
Kuhbacher, T., Ott, S. J., Helwig, U., Mimura, T., Rizzello, F., Kleessen, B., et al. (2006). Bacterial and fungal microbiota in relation to probiotic therapy (VSL#3) in pouchitis. Gut, 55(6), 833–841. https://doi.org/10.1136/gut.2005.078303.
Liu, F., Li, J., Wu, F., Zheng, H., Peng, Q., & Zhou, H. (2019). Altered composition and function of intestinal microbiota in autism spectrum disorders: A systematic review. Translational psychiatry, 9(1), 43. https://doi.org/10.1038/s41398-019-0389-6.
Lord, C., & Bishop, S. L. (2015). Recent advances in autism research as reflected in DSM-5 criteria for autism spectrum disorder. Annual Review of Clinical Psychology, 11, 53–70. https://doi.org/10.1146/annurev-clinpsy-032814-112745.
Macfarlane, S., & Dillon, J. F. (2007). Microbial biofilms in the human gastrointestinal tract. Journal of Applied Microbiology, 102(5), 1187–1196. https://doi.org/10.1111/j.1365-2672.2007.03287.x.
Marra, A. R., Opilla, M., Edmond, M. B., & Kirby, D. F. (2007). Epidemiology of bloodstream infections in patients receiving long-term total parenteral nutrition. Journal of Clinical Gastroenterology, 41(1), 19–28. https://doi.org/10.1097/01.mcg.0000212606.13348.f7.
Meltzer, A., & Van de Water, J. (2017). The role of the immune system in autism spectrum disorder. Neuropsychopharmacology, 42(1), 284–298. https://doi.org/10.1038/npp.2016.158.
Noto, A., Fanos, V., Barberini, L., Grapov, D., Fattuoni, C., Zaffanello, M., et al. (2014). The urinary metabolomics profile of an Italian autistic children population and their unaffected siblings. The Journal of Maternal-Fetal & Neonatal Medicine, 27(Suppl 2), 46–52. https://doi.org/10.3109/14767058.2014.954784.
Ormstad, H., Bryn, V., Verkerk, R., Skjeldal, O. H., Halvorsen, B., Saugstad, O. D., et al. (2018). Serum tryptophan, tryptophan catabolites and brain-derived neurotrophic factor in subgroups of youngsters with autism spectrum disorders. CNS & Neurological Disorders: Drug Targets, 17(8), 626–639. https://doi.org/10.2174/1871527317666180720163221.
Pais, P., Costa, C., Cavalheiro, M., Romao, D., & Teixeira, M. C. (2016). Transcriptional control of drug resistance, virulence and immune system evasion in pathogenic fungi: A cross-species comparison. Frontiers in Cellular and Infection Microbiology, 6, 131. https://doi.org/10.3389/fcimb.2016.00131.
Parks, D. H., Tyson, G. W., Hugenholtz, P., & Beiko, R. G. (2014). STAMP: Statistical analysis of taxonomic and functional profiles. Bioinformatics, 30(21), 3123–3124. https://doi.org/10.1093/bioinformatics/btu494.
Reichelt, K. L., & Knivsberg, A. M. (2009). The possibility and probability of a gut-to-brain connection in autism. Annals of Clinical Psychiatry, 21(4), 205–211.
Rhee, S. H., Pothoulakis, C., & Mayer, E. A. (2009). Principles and clinical implications of the brain-gut-enteric microbiota axis. Nature Reviews Gastroenterology & Hepatology, 6(5), 306–314. https://doi.org/10.1038/nrgastro.2009.35.
Rizzetto, L., Ifrim, D. C., Moretti, S., Tocci, N., Cheng, S. C., Quintin, J., et al. (2016). Fungal chitin induces trained immunity in human monocytes during cross-talk of the host with Saccharomyces cerevisiae. Journal of Biological Chemistry, 291(15), 7961–7972. https://doi.org/10.1074/jbc.M115.699645.
Rosenfeld, C. S. (2015). Microbiome disturbances and autism spectrum disorders. Drug Metabolism and Disposition, 43(10), 1557–1571. https://doi.org/10.1124/dmd.115.063826.
Sanata, B., Salam, O. A., Ibrahim, S., Adama, Z., Mamoudou, C., Simplice, K. D., et al. (2014). Digestive fungal flora in asymptomatic subjects in Bobo-Dioulasso, Burkina Faso. Asian Pacific Journal of Tropical Biomedicine, 4(8), 659–662. https://doi.org/10.12980/apjtb.4.201414b27.
Sauer, A. K., Bockmann, J., Steinestel, K., Boeckers, T. M., & Grabrucker, A. M. (2019). Altered intestinal morphology and microbiota composition in the autism spectrum disorders associated SHANK3 mouse model. International Journal of Molecular Sciences, 20(9), 2134. https://doi.org/10.3390/ijms20092134.
Severance, E. G., Alaedini, A., Yang, S., Halling, M., Gressitt, K. L., Stallings, C. R., et al. (2012). Gastrointestinal inflammation and associated immune activation in schizophrenia. Schizophrenia Research, 138(1), 48–53. https://doi.org/10.1016/j.schres.2012.02.025.
Severance, E. G., Gressitt, K. L., Stallings, C. R., Katsafanas, E., Schweinfurth, L. A., Savage, C. L. G., et al. (2017). Probiotic normalization of Candida albicans in schizophrenia: A randomized, placebo-controlled, longitudinal pilot study. Brain, Behavior, and Immunity, 62, 41–45. https://doi.org/10.1016/j.bbi.2016.11.019.
Smith-Brown, P., Morrison, M., Krause, L., & Davies, P. S. (2016). Dairy and plant based food intakes are associated with altered faecal microbiota in 2 to 3 year old Australian children. Scientific Reports, 6, 32385. https://doi.org/10.1038/srep32385.
Stanzani, M., Orciuolo, E., Lewis, R., Kontoyiannis, D. P., Martins, S. L., St John, L. S., et al. (2005). Aspergillus fumigatus suppresses the human cellular immune response via gliotoxin-mediated apoptosis of monocytes. Blood, 105(6), 2258–2265. https://doi.org/10.1182/blood-2004-09-3421.
Strati, F., Cavalieri, D., Albanese, D., De Felice, C., Donati, C., Hayek, J., et al. (2017). New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome, 5(1), 24. https://doi.org/10.1186/s40168-017-0242-1.
Suhr, M. J., Banjara, N., & Hallen-Adams, H. E. (2016). Sequence-based methods for detecting and evaluating the human gut mycobiome. Letters in Applied Microbiology, 62(3), 209–215. https://doi.org/10.1111/lam.12539.
Sun, X., Allison, C., Wei, L., Matthews, F. E., Auyeung, B., Wu, Y. Y., et al. (2019). Autism prevalence in China is comparable to Western prevalence. Molecular Autism, 10, 7. https://doi.org/10.1186/s13229-018-0246-0.
Ukhanova, M., Wang, X., Baer, D. J., Novotny, J. A., Fredborg, M., & Mai, V. (2014). Effects of almond and pistachio consumption on gut microbiota composition in a randomised cross-over human feeding study. British Journal of Nutrition, 111(12), 2146–2152. https://doi.org/10.1017/s0007114514000385.
Wang, L., Christophersen, C. T., Sorich, M. J., Gerber, J. P., Angley, M. T., & Conlon, M. A. (2011). Low relative abundances of the mucolytic bacterium Akkermansia muciniphila and Bifidobacterium spp. in feces of children with autism. Applied and Environmental Microbiology, 77(18), 6718–6721. https://doi.org/10.1128/aem.05212-11.
Williams, B. L., Hornig, M., Parekh, T., & Lipkin, W. I. (2012). Application of novel PCR-based methods for detection, quantitation, and phylogenetic characterization of Sutterella species in intestinal biopsy samples from children with autism and gastrointestinal disturbances. MBio, 3(1), 1–11. https://doi.org/10.1128/mBio.00261-11.
Wilson, D. (2017). A tale of two yeasts: Saccharomyces cerevisiae as a therapeutic against candidiasis. Virulence, 8(1), 15–17. https://doi.org/10.1080/21505594.2016.1230580.
Zheng, Z., Zhu, T., Qu, Y., & Mu, D. (2016). Blood glutamate levels in autism spectrum disorder: A systematic review and meta-analysis. PLoS ONE, 11(7), e0158688. https://doi.org/10.1371/journal.pone.0158688.
Zimmermann, K., Haas, A., & Oxenius, A. (2012). Systemic antibody responses to gut microbes in health and disease. Gut Microbes, 3(1), 42–47. https://doi.org/10.4161/gmic.19344.
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This work was supported by the Development Fund for Shanghai Talents (Grant Number 201567).
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HZ designed the project. Sample collection was performed by RZ and QZ. DNA extraction and sequencing was performed by MD and MG. Bioinformatics analysis was performed by RZ and YW. The first draft of the manuscript was written by RZ, YW and HZ. All authors read and approved the final manuscript.
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Zou, R., Wang, Y., Duan, M. et al. Dysbiosis of Gut Fungal Microbiota in Children with Autism Spectrum Disorders. J Autism Dev Disord 51, 267–275 (2021). https://doi.org/10.1007/s10803-020-04543-y
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DOI: https://doi.org/10.1007/s10803-020-04543-y