Advertisement

Gut Microbiome and Sex Bias in Autism Spectrum Disorders

  • 24 Accesses

Abstract

Purpose of Review

Autism spectrum disorders (ASD) express as impaired social interactions and stereotypes. The gut microbiome which is remarkably different in ASD compared with controls may contribute to the sex bias of this disorder, with females being less vulnerable to clinically present autism. This review aims to understand the role of gut microbiota and female sex hormone in the sex bias of autism.

Recent Findings

Recent evidence proved that transplanted gut microbiota from autistic donors but not healthy controls into germ-free mice were effective in inducing autistic features. Moreover selective probiotic known to be more abundant in females than males was effective as a treatment strategy.

Summary

The higher autistic phenotypes in males compared with females could be attributed to the protective effect of estrogen, the higher diversity and predominance of probiotics in females, the lower liability of females to develop leaky gut, neuroinflammation, and excitotoxicity as etiological mechanisms.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 99

This is the net price. Taxes to be calculated in checkout.

Fig. 1
Fig. 2
Fig. 3

Abbreviations

ASD:

Autism spectrum disorders

LPO:

Lipopolysaccharides

MEs:

Microbiota epitopes

MIA:

Maternal immune activation

MTT:

Microbiota transfer therapy

GABA:

γ-Aminobutyric acid

ZO-1:

Zonula occluden-1

PRSS:

Trypsin-like activity protein

References

    Papers of particular interest, published recently, have been highlighted as: • Of importance

    1. 1.

      Harrop,C., Jones, D., Zheng, S., Nowell, S.W., Boyd, B.A., Sasson, N., 2018. Sex differences in social attention in autism spectrum disorder. Autism Res 11 (9), 1264–1275.

    2. 2.

      Tillmann J, Ashwood K, Absoud M, Bölte S, Bonnet-Brilhault F, Buitelaar JK, et al. Evaluating sex and age differences in ADI-R and ADOS scores in a large autism spectrum disorders European multi-site sample of individuals with autism spectrum disorder. J AutismDev Disord. 2018;48(7):2490–505.

    3. 3.

      Elie-Fortier J, Braun C. Sex differences in secondary autism spectrum disorders: differential risk by sex, neurologic load and ascertainment bias. Neurol Psychiatry Brain Res. 2019;32:14–21. https://doi.org/10.1016/j.npbr.2019.03.003.

    4. 4.

      Miles JH, Hillman RE. Value of a clinical morphology examination in autism. Am J Med Genet. 2000;91:245–53.

    5. 5.

      Gillberg C, Cederlund M, Lamberg K, Zeijlon L. Brief report: “the autism epidemic”. The registered prevalence of autism in a Swedish urban area. J Autism Dev Disord. 2006;36:429–35.

    6. 6.

      Supekar K, Menon V. Sex differences in structural organization of motor systems and their dissociable links with repetitive/restricted behaviors in children with autism. Molecular Autism. 2015;6(1):50–60.

    7. 7.

      El-Ansary A, Shafi Bhat R. Targeting gut microbiota as a possible therapeutic intervention in autism. In: Autism 360° 1st edition. Edited by: Undurti Das, Neophytos Papaneophytou, and Tatyana El-Kour. Academic Press. 2019.

    8. 8.

      Sharon G, Cruz NJ, Kang DW, Gandal MJ, Wang B, Kim YM, et al. Human gut microbiota from autism spectrum disorders promote behavioral symptoms in mice. Cell. 2019;177(6):1600–1618.e17. https://doi.org/10.1016/j.cell.2019.05.004.

    9. 9.

      Hatheway CL. Toxigenic clostridia. Clin Microbiol Rev. 1990;3:66–98.

    10. 10.

      • Kushak RI, Winter HS. Intestinal microbiota, metabolome and gender dimorphism in autism spectrum disorders. Res Autism Spectr Disord. 2018;49:65–74. https://doi.org/10.1016/j.rasd.2018.01.009This review highlights the contribution of gut microbiota as etiological mechanism related to the vulnerability of males to clinically present autism either directly through bacterial metabolites or indirectly through epigenetic factors.

    11. 11.

      Schaafsma SM, Gagnidze K, Reyes A, Norstedt N, Månsson K, Francis K, et al. Sex-specific gene-environment interactions underlying ASD-like behaviors. Proc Natl Acad Sci U S A. 2017;114:1383–8.

    12. 12.

      Shin JH, Park YH, Sim M, Kim SA, Joung H, Shin DM. Serum level of sex steroid hormone is associated with diversity and profiles of human gut microbiome. Res Microbiol. 2019;30:S0923–2508. https://doi.org/10.1016/j.resmic.2019.03.003.

    13. 13.

      Moreno-Indias I, Sánchez-Alcoholado L, Sánchez-Garrido MÁ, Martín-Núñez GM, Pérez-Jiménez F, Tena-Sempere M, et al. Neonatal androgen exposure causes persistent gut microbiota dysbiosis related to metabolic disease in adult female rats. Endocrinology. 2016;157(12):4888–98. https://doi.org/10.1210/en.2016-1317.

    14. 14.

      Wiley NC, Dinan TG, Ross RP, Stanton C, Clarke G, Cryan JF. The microbiota-gut-brain axis as a key regulator of neural function and the stress response: implications for human and animal health. J Anim Sci. 2017;95(7):3225–46. https://doi.org/10.2527/jas.2016.1256.

    15. 15.

      Markle JG, Frank DN, Adeli K, von Bergen M, Danska JS. Microbiome manipulation modifies sex-specific risk for autoimmunity. Gut Microbes. 2014;5:485–93. https://doi.org/10.4161/gmic.29795.

    16. 16.

      Rincel M, Aubert P, Chevalier J, Grohard PA, Basso L, Monchaux de Oliveira C, Helbling JC, Lévy É, Chevalier G, Leboyer M, Eberl G, Layé S, Capuron L, Vergnolle N, Neunlist M, Boudin H, Lepage P, Darnaudéry M. Multi-hit early life adversity affects gut microbiota, brain and behavior in a sex-dependent manner. Brain. Behav. Immun. 2019; 1591(18):30570–30571. DOI: https://doi.org/10.1016/j.bbi.2019.03.006.

    17. 17.•

      Ferri SL, Abel T, Brodkin ES. Sex differences in autism spectrum disorders: a review. Curr Psychiatry Rep. 2018;20(2):9. https://doi.org/10.1007/s11920-018-0874-2This review highlights current theories of sex bias in autism through considering multiple environmental, genetic, and epigenetic factors. Most interestingly, it discusses the threshold liability model and female sex hormone protective effect in neurodevelopmental disorders.

    18. 18.

      Polyak A, Rosenfeld JA, Girirajan S. An assessment of sex bias in neurodevelopmental disorders. Genome Medicine. 2015;7(1):94. https://doi.org/10.1186/s13073-015-0216-5.

    19. 19.

      Elie-Fortiera J and Braunb C. Sex differences in secondary autism spectrum disorders: differential risk by sex, neurologic load and ascertainment bias. Neurology, Psychiatry. and Brain. Research. 2019; 32: 14–21. DOI:https://doi.org/10.1016/j.npbr.2019.03.003.

    20. 20.

      Wang M, Zhou J, He F, Cai C, Wang H, Wang Y, et al. Alteration of gut microbiota-associated epitopes in children with autism spectrum disorders. Brain Behav Immun. 2019;75:192–9. https://doi.org/10.1016/j.bbi.2018.10.006.

    21. 21.

      Li N, Yang J, Zhang J, Liang C, Wang Y, Chen B, et al. Correlation of gut microbiome between ASD children and mothers and potential biomarkers for risk assessment. Genomics Proteomics Bioinformatics. 2019;17(1):26–38. https://doi.org/10.1016/j.gpb.2019.01.002.

    22. 22.

      Buffington SA, Di Prisco GV, Auchtung TA, Ajami NJ, Petrosino JF, Costa-Mattioli M. Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring. Cell. 2016;165:1762–75. https://doi.org/10.1016/j.cell.2016.06.001.

    23. 23.

      Kang DW, Adams JB, Gregory AC, Borody T, Chittick L, Fasano A, et al. Microbiota transfer therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome. 2017;5(1):10. https://doi.org/10.1186/s40168-016-0225-7.

    24. 24.

      Choi GB, Yim YS, Wong H, Kim S, Kim H, Kim SV, et al. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science. 2016;351(6276):933–9. https://doi.org/10.1126/science.aad0314.

    25. 25.

      Noto A, Fanos V, Barberini L, Grapov D, Fattuoni C, Zaffanello M, et al. The urinary metabolomics profile of an Italian autistic children population and their unaffected siblings. J Matern Fetal Neonatal Med. 2014;27(sup2):46–52. https://doi.org/10.3109/14767058.2014.954784.

    26. 26.

      Kaluzna-Czaplinska J, Blaszczyk S. The level of arabinitol in autistic children after probiotic therapy. Nutrition. 2012;28:124–6. https://doi.org/10.1016/j.nut.2011.08.002.

    27. 27.

      Kim S, Kim H, Yim YS, Ha S, Atarashi K, Tan TG, et al. Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring. Nature. 2017;549(7673):528–32. https://doi.org/10.1038/nature23910.

    28. 28.

      Hughes HK, Ashwood P. Anti-Candida albicans IgG antibodies in children with autism spectrum disorders. Front Psychiatry. 2018;9:627. https://doi.org/10.3389/fpsyt.2018.00627.

    29. 29.

      Theoharides TC, Tsilioni I, Patel AB, Doyle R. Atopic diseases and inflammation of the brain in the pathogenesis of autism spectrum disorders. Transl Psychiatry. 2016;6:e844. https://doi.org/10.1038/tp.2016.77.

    30. 30.

      Gupta RK, Gupta RC. Biomarkers of blood-brain barrier dysfunction. In: Biomarkers in toxicology (second edition). 2019, pp 997–1012.

    31. 31.

      Scafuri B, Varriale A, Facchiano A, D’Auria S, Raggi ME, Marabotti A. Binding of mycotoxins to proteins involved in neuronal plasticity: a combined in silico/wet investigation. Sci Rep. 2017 Nov;7(1):15156. https://doi.org/10.1038/s41598-017-15148-4.

    32. 32.

      Burrus CJ. A biochemical rationale for the interaction between gastrointestinal yeast and autism. Med Hypotheses. 2012;79:784–5. https://doi.org/10.1016/j.mehy.2012.08.029.

    33. 33.

      Al-Suwailem E, Abdi S, El-Ansary A. Sex differences in the glutamate signaling pathway in juvenile rats. J Neurosci Res. 2018;96(3):459–66. https://doi.org/10.1002/jnr.24144.

    34. 34.

      Mezzelani A, Raggi ME, Marabotti A, Milanesi L. Ochratoxin A as possible factor trigging autism and its male prevalence via epigenetic mechanism. Nutr Neurosci. 2016;19:43–6. https://doi.org/10.1179/1476830515Z.000000000186.

    35. 35.

      Tabouy L, Getselter D, Ziv O, Karpuj M, Tabouy T, Lukic I, et al. Dysbiosis of microbiome and probiotic treatment in a genetic model of autism spectrum disorders. Brain Behav Immun. 2018;73:310–9. https://doi.org/10.1016/j.bbi.2018.05.015.

    36. 36.

      Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG, et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A. 2011;108(38):16050–5. https://doi.org/10.1073/pnas.1102999108.

    37. 37.

      You YH, Qin ZQ, Zhang HL, Yuan ZH, Yu X. MicroRNA-153 promotes brain-derived neurotrophic factor and hippocampal neuron proliferation to alleviate autism symptoms through inhibition of JAK-STAT pathway by LEPR. Biosci Rep. 2019;11:BSR20181904. https://doi.org/10.1042/BSR20181904.

    38. 38.

      Janik R, Thomason LAM, Stanisz AM, Forsythe P, Bienenstock J, Stanisz GJ. Magnetic resonance spectroscopy reveals oral Lactobacillus promotion of increases in brain GABA, N-acetyl aspartate and glutamate. Neuroimage. 2016;125:988–95. https://doi.org/10.1016/j.neuroimage.2015.11.018.

    39. 39.

      Coretti L, Cristiano C, Florio E, Scala G, Lama A, Keller S, et al. Sex-related alterations of gut microbiota composition in the BTBR mouse model of autism spectrum disorders. Sci Rep. 2017;7:45356. https://doi.org/10.1038/srep45356.

    40. 40.

      de Theije CG, Wopereis H, Ramadan M, van Eijndthoven T, Lambert J, Knol J, et al. Altered gut microbiota and activity in a murine model of autism spectrum disorders. Brain Behav Immun. 2014;37:197–206. https://doi.org/10.1016/j.bbi.2013.12.005.

    41. 41.

      Konikoff T, Gophna U. Oscillospira: a central, enigmatic component of the human gut microbiota. Trends Microbiol. 2016;24(7):523–4. https://doi.org/10.1016/j.tim.2016.02.015.

    42. 42.

      Kratsman N, Getselter D, Elliott E. Sodium butyrate attenuates social behavior deficits and modifies the transcription of inhibitory/excitatory genes in the frontal cortex of an autism model. Neuropharmacology. 2016;102:136–45. https://doi.org/10.1016/j.neuropharm.2015.11.003.

    43. 43.

      Newell C, Bomhof MR, Reimer RA, Hittel DS, Rho JM, Shearer J. Ketogenic diet modifies the gut microbiota in a murine model of autism spectrum disorders. Mol Autism. 2016;7(1):37. https://doi.org/10.1186/s13229-016-0099-3.

    44. 44.

      Olson CA, Vuong HE, Yano JM, Liang QY, Nusbaum DJ, Hsiao EY. The gut microbiota mediates the anti-seizure effects of the ketogenic diet. Cell. 2018;173(7):1728–1741.e13. https://doi.org/10.1016/j.cell.2018.04.027.

    45. 45.

      Olson CA, Vuong HE, Yano JM, Liang QY, Nusbaum DJ, Hsiao EY. The gut microbiota mediates the anti-seizure effects of the ketogenic diet. Cell. 2018;174(2):497. https://doi.org/10.1016/j.cell.2018.06.051.

    46. 46.

      Zak-Gołąb A, Kocełak P, Aptekorz M, Zientara M, Juszczyk L, Martirosian G, et al. Gut microbiota, microinflammation, metabolic profile, and zonulin concentration in obese and normal weight subjects. Int J Endocrinol. 2013;674106. https://doi.org/10.1155/2013/674106.

    47. 47.

      Fasano A, Not T, Wang W, Uzzau S, Berti I, Tommasini A, et al. Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease. Lancet. 2000;355(9214):1518–9. https://doi.org/10.1016/S0140-6736(00)02169-3.

    48. 48.

      Kelly JR, Kennedy PJ, Cryan JF, Dinan TG, Clarke G, Hyland NP. Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. Front Cell Neurosci. 2015;9:392. https://doi.org/10.3389/fncel.2015.00392.

    49. 49.

      Michielan A, D’Incà R. Intestinal permeability in inflammatory bowel disease: pathogenesis, clinical evaluation, and therapy of leaky gut. Mediat Inflamm. 2015;2015:628157. https://doi.org/10.1155/2015/628157.

    50. 50.

      Fasano A. Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiol Rev. 2011;91:151–75. https://doi.org/10.1152/physrev.00003.2008.

    51. 51.

      Mörkl S, Lackner S, Meinitzer A, Mangge H, Lehofer M, Halwachs B, et al. Gut microbiota, dietary intakes and intestinal permeability reflected by serum zonulin in women. Eur J Nutr. 2018;57(8):2985–97. https://doi.org/10.1007/s00394-018-1784-0.

    52. 52.

      Sturgeon C, Fasano A. Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inflammatory diseases. Tissue Barriers. 2016;4(4):e1251384. https://doi.org/10.1080/21688370.2016.1251384.

    53. 53.

      Ajamian M, Steer D, Rosella G, Gibson PR. Serum zonulin as a marker of intestinal mucosal barrier function: may not be what it seems. PLoS One. 2019;14(1):e0210728. https://doi.org/10.1371/journal.pone.0210728.

    54. 54.

      Esnafoglu E, Cırrık S, Ayyıldız SN, Erdil A, Ertürk EY, Daglı A, et al. Increased serum zonulin levels as an intestinal permeability marker in autistic subjects. J Pediatr. 2017;188:240–4. https://doi.org/10.1016/j.jpeds.2017.04.004.

    55. 55.

      Fiorentino M, Sapone A, Senger S, Camhi SS, Kadzielski SM, Buie TM, Kelly DL, Cascella N, Fasano A. Blood-brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders. Mol Autism 2016; 7:49. eCollection 2016. DOI: https://doi.org/10.1186/s13229-016-0110-z.

    56. 56.

      Fowlie G, Cohen N, Ming X. The perturbance of microbiome and gut-brain axis in autism spectrum disorders. Int J Mol Sci. 2018;19(8):E2251. https://doi.org/10.3390/ijms19082251.

    57. 57.

      Stein TD, Alvarez VE, McKee AC. Concussion in chronic traumatic encephalopathy. Curr Pain Headache Rep. 2015;19(10):47–6. https://doi.org/10.1007/s11916-015-0522-z.

    58. 58.

      Emanuele E, Orsi P, Boso M, Broglia D, Brondino N, Barale F, et al. Low-grade endotoxemia in patients with severe autism. Neurosci Lett. 2010;471(3):162–5. https://doi.org/10.1016/j.neulet.2010.01.033.

    59. 59.•

      Leech B, Schloss J, Steel A. Association between increased intestinal permeability and diseases; a systemic review. Advances. In integrative. Medicine. 2019;6(1):23–34. https://doi.org/10.1016/j.aimed.2018.08.003This review highlights the relationship between leaky gut as co-morbidity in autism and sex bias through considering the role of zonulin in inducing abnormal intestinal permeability in males compared with females.

    60. 60.

      Özyurt G, Öztürk Y, Appak YÇ, Arslan FD, Baran M, Karakoyun İ, et al. Increased zonulin is associated with hyperactivity and social dysfunctions in children with attention deficit hyperactivity disorder. Compr Psychiatry. 2018;87:138–42. https://doi.org/10.1016/j.comppsych.2018.10.006.

    61. 61.

      Rose DR, Yang H, Serena G, Sturgeon C, Ma B, Careaga M, et al. Differential immune responses and microbiota profiles in children with autism spectrum disorders and co-morbid gastrointestinal symptoms. Brain Behav Immun. 2018;70:354–68. https://doi.org/10.1016/j.bbi.2018.03.025.

    62. 62.

      Zhou Z, Zhang L, Ding M, Luo Z, Yuan S, Bansal MB, et al. Estrogen decreases tight junction protein ZO-1 expression in human primary gut tissues. Clin Immunol. 2017;183:174–80. https://doi.org/10.1016/j.clim.2017.08.019.

    63. 63.

      Laura AD, Hothi H, Battisti C, Cerquiglini A, Henckel J, Skinner J, et al. Wear of dual-mobility cups: a review article. Int Orthop. 2017;41(3):625–33. https://doi.org/10.1007/s00264-016-3326-9.

    64. 64.

      Hiller RM, Young RL, Weber N. Sex differences in autism spectrum disorders based on DSM-5 criteria: evidence from clinician and teacher reporting. J Abnorm Child Psychol. 2014;42(8):1381–93. https://doi.org/10.1007/s10802-014-9881-x.

    65. 65.

      Cooper E, Schexnayder L, Meaux T. Sunburn recall reaction and mucositis secondary to methotrexate toxicity. Skinmed. 2018;16(5):340–1 eCollection 2018. https://www.ncbi.nlm.nih.gov/pubmed/30413231.

    66. 66.

      Rolland-Fourcade C, Denadai-Souza A, Cirillo C, Lopez C, Jaramillo JO, Desormeaux C, et al. Epithelial expression and function of trypsin-3 in irritable bowel syndrome. Gut. 2017;66(10):1767–78. https://doi.org/10.1136/gutjnl-2016-312094.

    67. 67.

      Tomova A, Husarova V, Lakatosova S, Bakos J, Vlkova B, Babinska K, et al. Gastrointestinal microbiota in children with autism in Slovakia. Physiol Behav. 2015;138:179–87. https://doi.org/10.1016/j.physbeh.2014.10.033.

    68. 68.

      Grossi E, Melli S, Dunca D, Terruzzi V. Unexpected improvement in core autism spectrum disorder symptoms after long-term treatment with probiotics. SAGE Open Med Case Rep. 2016;4. https://doi.org/10.1177/2050313X16666231.

    69. 69.

      Sichel J. Improvements in gastrointestinal symptoms among children with autism spectrum disorders receiving the Delpro probiotic and immunomodulator formulation. J Probiot Health. 2013;1. https://doi.org/10.4172/2329-8901.1000102.

    70. 70.

      Anu S. On dysbiosis and biofilm production in autism. AIMS Mol Sci. 2018;5:160–5.

    71. 71.

      Lee JY, Kim N, Nam RH, Sohn SH, Lee SM, Choi D, et al. Probiotics reduce repeated water avoidance stress-induced colonic microinflammation in Wistar rats in a sex-specific manner. PLoS One. 2017;12(12):e0188992. https://doi.org/10.1371/journal.pone.0188992.

    72. 72.

      McCabe LR, Irwin R, Schaefer L, Britton RA. Probiotic use decreases intestinal inflammation and increases bone density in healthy male but not female mice. J Cell Physiol. 2013;228:1793–8. https://doi.org/10.1002/jcp.24340.

    73. 73.

      Miao J, Lang C, Kang Z, Zhu H, Wang S, Li M. Oral administration of fermented milk supplemented with synbiotics can influence the physiological condition of Wistar rats in a dose-sensitive and sex-specific manner. Biosci Microbiota Food Health. 2016;35:89–96. https://doi.org/10.12938/bmfh.2015-013.

    74. 74.

      He J, Wang W, Wu Z, Pana D, Guo Y, Cai Z, et al. Effect of Lactobacillus reuteri on intestinal microbiota and immune parameters: involvement of sex differences. J Funct Foods. 2019;53:36–43. https://doi.org/10.1101/312678.

    Download references

    Author information

    Correspondence to Afaf El-Ansary.

    Ethics declarations

    Human and Animal Rights and Informed Consent

    This article does not contain any studies with human or animal subjects performed by any of the authors.

    Conflict of Interest

    The authors declare that they have no conflict of interest.

    Additional information

    Publisher’s Note

    Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

    This article is part of the Topical Collection on Brain and Microbiome

    Rights and permissions

    Reprints and Permissions

    About this article

    Verify currency and authenticity via CrossMark

    Cite this article

    El-Ansary, A., Bhat, R.S. & Zayed, N. Gut Microbiome and Sex Bias in Autism Spectrum Disorders. Curr Behav Neurosci Rep (2020) doi:10.1007/s40473-020-00197-3

    Download citation

    Keywords

    • Autism spectrum disorders
    • Sex bias
    • Gut microbiota
    • Leaky gut
    • Glutamate excitotoxicity