Gut-brain axis and the risk of autism spectrum disorders

Weronika Wierzchanowska, Tomasz Iwanicki, Tomasz Nowak, Alicja Jarosz, Grzegorz Boryczka, Marek Waluga


Autism spectrum disorders (ASD) are a complex group of developmental pathologies characterized by the disorders of social interaction and communication, along with repetitive restrictive behavior. Many factors are associated with the development of ASD, including genetic and environmental factors such as nutritional deficiencies, infections, immune system dysfunctions, and allergies. The human gut microbiome is composed of communities of bacteria, viruses, and fungi that influence the central nervous system (CNS). Dysbiosis is defined as an imbalance or maladaptation in the gut microbial community which favors many pathological states and may be associated with some diseases. The changes in microbiota composition in children with ASD may contribute to both gastrointestinal and CNS symptoms. The disorders of the gut-brain axis signaling appear to affect neuropsychiatric disorders, including autism and ASD. The prevention and treatment of dysbiosis in ASD involves modification of the gut microbiome using the supplementation with probiotics – a live active culture.


autism spectrum disorders; gut-brain axis; microbiome; dysbiosis; probiotics; postbiotics

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Fattorusso A, Di Genova L, Dell’Isola GB, Mencaroni E, Esposito S. Autism spectrum disorders and the gut microbiota. Nutrients 2019;11(3):521. doi: 10.3390/nu11030521.

Doernberg E, Hollander E. Neurodevelopmental disorders (ASD and ADHD): DSM-5, ICD-10, and ICD-11. CNS Spectr 2016;21(4):295-9. doi: 10.1017/S1092852916000262.

Rish N, Hoffmann TJ, Anderson M, Croen LA, Grether JK, Windham GC. Familial recurrence of autism spectrum disorder: evaluating genetic and environmental contributions. Am J Psychiatry 2014;171(11):1206-13. doi: 10.1176/appi.ajp.2014.13101359.

Adams JB, Johansen LJ, Powell LD, Quig D, Rubin RA. Gastrointestinal flora and gastrointestinal status in children with autism – comparisons to typical children and correlation with autism severity. BMC Gastroenterol 2011;11:22. doi: 10.1186/1471-230X-11-22.

Roussin L, Prince N, Perez-Pardo P, Kraneveld AD, Rabot S, Naudon L. Role of the gut microbiota in the pathophysiology of autism spectrum disorder: clinical and preclinical evidence. Microorganisms 2020;8(9):1369. doi: 10.3390/microorganisms8091369.

Wang L, Conlon MA, Christophersen CT, Sorich MJ, Angley MT. Gastrointestinal microbiota and metabolite biomarkers in children with autism spectrum disorders. Biomark Med 2014;8(3):331-44. doi: 10.2217/bmm.14.12.

Garcia-Gutierrez E, Narbad A, Rodríguez JM. Autism spectrum disorder associated with gut microbiota at immune, metabolomic, and neuroactive level. Front Neurosci 2020;14:578666. doi: 10.3389/fnins.2020.578666.

De Angelis M, Francavilla R, Piccolo M, De Giacomo A, Gobbetti M. Autism spectrum disorders and intestinal microbiota. Gut Microbes 2015;6(3):207-13. doi: 10.1080/19490976.2015.1035855.

Navarro F, Liu Y, Rhoads JM. Can probiotics benefit children with autism spectrum disorders? World J Gastroenterol 2016;22(46):10093-102. doi: 10.3748/wjg.v22.i46.10093.

Eshraghi R, Davies C, Iyengar R, Perez L, Mittal R, Eshraghi AA. Gut-induced inflammation during development may compromise the blood-brain barrier and predispose to autism spectrum disorder. J Clin Med 2020;10(1):27. doi: 10.3390/jcm10010027.

Flint HJ. The impact of nutrition on the human microbiome. Nutr Rev 2012;70 Suppl 1:10-3. doi: 10.1111/j.1753-4887.2012.00499.x.

Generoso JS, Giridharan VV, Lee J, Macedo D, Barichello T. The role of the microbiota-gut-brain axis in neuropsychiatric disorders. Braz J Psychiatry 2021;43(3):293-305. doi: 10.1590/1516-4446-2020-0987.

Q J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010;464(7285):59-65. doi: 10.1038/nature08821.

Grice EA, Segre JA. The human microbiome: our second genome. Annu Rev Genomics Hum Genet 2012;13:151-70. doi: 10.1146/annurev-genom-090711-163814.

Rose C, Parker A, Jefferson B, Cartmell E. The characterization of feces and urine: a review of the literature to inform advanced treatment technology. Crit Rev Environ Sci Technol 2015;45(17):1827-79. doi: 10.1080/10643389.2014.1000761.

Dominguez-Bello M, Costello EK, Contreras M, Magris M, Hidalgo G, Fierer N, et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. PNAS 2010;107(26):11971-5. doi: 10.1073/pnas.1002601107.

Redondo-Useros N, Nova E, González-Zancada N, Díaz LE, Gómez-Martínez S, Marcos A. Microbiota and lifestyle: a special focus on diet. Nutrients 2020;12(6):1776. doi: 10.3390/nu12061776.

Hasan N, Yang H. Factors affecting the composition of the gut microbiota, and its modulation. PeerJ 2019;7:e7502. doi: 10.7717/peerj.7502.

Zhu X, Han Y, Du J, Liu R, Jin K, Yi W. Microbiota-gut-brain axis and the central nervous system. Oncotarget 2017;8(32):53829-38. doi: 10.18632/oncotarget.17754.

DeGruttola AK, Low D, Mizoguchi A, Mizoguchi E. Current understanding of dysbiosis in disease in human and animal models. Inflamm Bowel Dis 2016;22(5):1137-50. doi: 10.1097/MIB.0000000000000750.

Olesen SW, Alm EJ. Dysbiosis is not an answer. Nat Microbiol 2016;1:16228. doi: 10.1038/nmicrobiol.2016.228.

Finegold SM, Downes J, Summanen PH. Microbiology of regressive autism. Anaerobe 2012;18(2):260-2. doi: 10.1016/j.anaerobe.2011.12.018.

Hua X, Zhu J, Yang T, Guo M, Li Q, Chen J, et al. The gut microbiota and associated metabolites are altered in sleep disorder of children with autism spectrum disorders. Front Psychiatry 2020;11:855. doi: 10.3389/fpsyt.2020.00855.

Silva YP, Bernardi A, Frozza RL. The Role of short-chain fatty acids from gut microbiota in gut-brain communication. Front Endocrinol (Lausanne) 2020;11:25. doi: 10.3389/fendo.2020.00025.

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. doi: 10.1016/j.physbeh.2014.10.033.

Ding X, Xu Y, Zhang X, Zhang L, Duan G, Song C, et al. Gut microbiota changes in patients with autism spectrum disorders. J Psychiatr Res 2020;129:149-59. doi: 10.1016/j.jpsychires.2020.06.032.

Iglesias-Vázquez L, Van Ginkel Riba G, Arija V, Canals J. Composition of gut microbiota in children with autism spectrum disorder: a systematic review and meta-analysis. Nutrients 2020;12(3):792. doi: 10.3390/nu12030792.

Williams BL, Hornig M, Parekh T, Ian Lipkin WI. 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 2012;3(1):e00261-11. doi: 10.1128/mBio.00261-11.

Finegold SM, Dowd SE, Gontcharova V, Liu C, Henley KE, Wolcott RD, et al. Pyrosenquencing study of fecal microflora of autistic and control children. Anaerobe 2010;16(4):444-53. doi: 10.1016/j.anaerobe.2010.06.008.

Ding HT, Taur Y, Walkup JT. Gut microbiota and autism: key concepts and findings. J Autism Dev Disord 2017;47(2):480-9. doi: 10.1007/s10803-016-2960-9.

Yang XL, Liang S, Zou MY, Sun CH, Han P, Jiang XT, et al. Are gastrointestinal and sleep problems associated with behavioral symptoms of autism spectrum disorder? Psychiatry Res 2018;259:229-35. doi: 10.1016/j.psychres.2017.10.040.

Argou-Cardozo I, Zeidán-Chuliá F. Clostridium bacteria and autism spectrum conditions: a systematic review and hypothetical contribution of environmental glyphosate levels. Med Sci (Basel) 2018;6(2):29. doi: 10.3390/medsci6020029.

Strati F, Cavalieri D, Albanese D, De Felice C, Donati C, Hayek J, et al. New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome 2017;5(1):24. doi: 10.1186/s40168-017-0242-1.

Rose S, Nyiazov DM, Rossignol DA, Goldenthal M, Kahler SG, Frye RE. Clinical and molecular characteristics of mitochondrial dysfunction in autism spectrum disorder. Mol Diagn Ther 2018;22(5):571-93. doi: 10.1007/s40291-018-0352-x.

Walker SJ, Beavers DP, Fortunato J, Krigsman A. A putative blood-based biomarker for autism spectrum disorder-associated ileocolitis. Sci Rep 2016;6:35820. doi: 10.1038/srep35820.

Doenyas C. Gut microbiota, inflammation, and probiotics on neural development in autism spectrum disorder. Neuroscience 2018;374:271-86. doi: 10.1016/j.neuroscience.2018.01.060.

Viggiano D, Ianiro G, Vanella G, Bibbò S, Bruno G, Simeone G, et al. Gut barrier in health and disease: focus on childhood. Eur Rev Med Pharmacol Sci 2015;19(6):1077-85.

Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T, et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 2013;155(7):1451-63. doi: 10.1016/j.cell.2013.11.024.

Maher P. Methylglyoxal, advanced glycation end products and autism: is there a connection? Med Hypotheses 2012;78(4):548-52. doi: 10.1016/j.mehy.2012.01.032.

Li Q, Han Y, Dy ABC, Hagerman RJ. The gut microbiota and autism spectrum disorders. Front Cell Neurosci 2017;11:120. doi: 10.3389/fncel.2017.00120.

Aschwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah I, Van de Water J. Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain Behav Immun 2011;25(1):40-5. doi: 10.1016/j.bbi.2010.08.003.

Cao X, Liu K, Liu J, Liu YW, Xu L, Wang H, et al. Dysbiotic gut microbiota and dysregulation of cytokine profile in children and teens with autism spectrum disorder. Front Neurosci 2021;15:635925. doi: 10.3389/fnins.2021.635925.

Holingue C, Newill C, Lee LC, Pasricha PJ, Fallin MD. Gastrointestinal symptoms in autism spectrum disorder: a review of the literature on ascertainment and prevalence. Autism Res 2018;11(1):24-36. doi: 10.1002/aur.1854.

Srikantha P, Mohajeri MH. The possible role of the microbiota-gut-brain-axis in autism spectrum disorder. Int J Mol Sci 2019;20(9):2115. doi: 10.3390/ijms20092115.

Marler S, Ferguson BJ, Lee EB, Peters B, Williams KC, McDonnell E, et al. Association of rigid-compulsive behavior with functional constipation in autism spectrum disorder. J Autism Dev Disord 2017;47(6):1673-81. doi: 10.1007/s10803-017-3084-6.

Asbjornsdottir B, Snorradottir H, Andresdottir E, Fasano A, Lauth B, Gudmundsson L, et al. Zonulin-dependent intestinal permeability in children diagnosed with mental disorders: a systematic review and meta-analysis. Nutrients 2020;12(7):1982. doi: 10.3390/nu12071982.

Kang DW, Park JG, Ilhan ZE, Wallstrom G, Labaer J, Adams JB, et al. Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children. PLoS One 2013;8(7):e68322. doi: 10.1371/journal.pone.0068322.

Macfabe DF. Short-chain fatty acid fermentation products of the gut microbiome: implications in autism spectrum disorders. Microb Ecol Health Dis 2012;23(19260):1-25. doi: 10.3402/mehd.v23i0.19260.

Alshammari MK, AlKhulaifi MM, Al Farraj DA, Somily AM, Albarrag AM. Incidence of Clostridium perfringens and its toxin genes in the gut of children with autism spectrum disorder. Anaerobe 2020;61:102114. doi: 10.1016/j.anaerobe.2019.102114.

Gabriele S, Sacco R, Cerullo S, Neri C, Urbani A, Tripi G, et al. Urinary p-cresol is elevated in young French children with autism spectrum disorder: a replication study. Biomarkers 2014;19(6):463-70. doi: 10.3109/1354750X.2014.936911.

MacFabe DF. Enteric short-chain fatty acids: microbial messengers of metabolism, mitochondria, and mind: implications in autism spectrum disorders. Microbial Ecol Health Dis 2015;26:28177. doi: 10.3402/mehd.v26.28177.

Tran SM, Mohajeri MH. The role of gut bacterial metabolites in brain development, aging and disease. Nutrients 2021;13(3):732. doi: 10.3390/nu13030732.

MacFabe DF, Cain NE, Boon F, Ossenkopp KP, Cain DP. Effects of the enteric bacterial metabolic product propionic acid on object-directed behavior, social behavior, cognition, and neuroinflammation in adolescent rats: Relevance to autism spectrum disorder. Behav Brain Res 2011;217(1):47-54. doi: 10.1016/j.bbr.2010.10.005.

Hong J, Jia Y, Pan S, Jia L, Li H, Han Z, et al. Butyrate alleviates high fat diet-induced obesity through activation of adiponectin-mediated pathway and stimulation of mitochondrial function in the skeletal muscle of mice. Oncotarget 2016;7(35):56071-82. doi: 10.18632/oncotarget.11267.

Shimmura C, Suda S, Tsuchiya KJ, Hashimoto K, Ohno K, Matsuzaki H, et al. Alteration of plasma glutamate and glutamine levels in children with high-functioning autism. PLoS One 2011;6(10):e25340. doi: 10.1371/journal.pone.0025340.

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 Suppl 2:46-52. doi: 10.3109/14767058.2014.954784.

Israelyan N, Margolis KG. Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders. Pharmacol Res 2018;132:1-6. doi: 10.1016/j.phrs.2018.03.020.

Marler S, Ferguson BJ, Lee EB, Peters B, Williams KC, McDonnell E, et al. Brief report: Whole blood serotonin levels and gastrointestinal symptoms in autism spectrum disorder. J Autism Dev Disord 2016;46(3):1124-30. doi: 10.1007/s10803-015-2646-8.

Golubeva AV, Joyce SA, Moloney G, Burokas A, Sherwin E, Arboleya S, et al. Microbiota-related changes in bile acid & tryptophan metabolism are associated with gastrointestinal dysfunction in a mouse model of autism. EBioMedicine 2017;24:166-78. doi: 10.1016/j.ebiom.2017.09.020.

de Theije CG, Wu J, da Silva SL, Kamphuis PJ, Garssen J, Korte SM, et al. Pathways underlying the gut-to-brain connection in autism spectrum disorders as future targets for disease management. Eur J Pharmacol 2011;668 Suppl 1:S70-80. doi: 10.1016/j.ejphar.2011.07.013.

Kraneveld AD, Szklany K, de Theije CG, Garssen J. Gut-to-brain axis in autism spectrum disorders: central role for the microbiome. Int Rev Neurobiol 2016;131:263-87. doi: 10.1016/bs.irn.2016.09.001.

Rose S, Bennuri SC, Murray KF, Buie T, Winter H, Frye RE. Mitochondrial dysfunction in the gastrointestinal mucosa of children with autism: A blinded case-control study. PLoS One 2017;12(10):e0186377. doi: 10.1371/journal.pone.0186377.

Ansel A, Rosenzweig JP, Zisman PD, Melamed M, Gesundheit B. Variation in Gene Expression in Autism Spectrum Disorders: An Extensive Review of Transcriptomic Studies. Front Neurosci 2017;10:601. doi: 10.3389/fnins.2016.00601.

Madore C, Leyrolle Q, Lacabanne C, Benmamar-Badel A, Joffre C, Nadjar A, et al. Neuroinflammation in autism: plausible role of maternal inflammation, dietary omega 3, and microbiota. Neural Plast 2016;2016:3597209. doi: 10.1155/2016/3597209.

Carter CJ, Blizard RA. Autism genes are selectively targeted by environmental pollutants including pesticides, heavy metals, bisphenol A, phthalates and many others in food, cosmetics or household products. Neurochem Int 2016;S0197-0186(16)30197-8. doi: 10.1016/j.neuint.2016.10.011.

Vuong HE, Hsiao EY. Emerging roles for the gut microbiome in autism spectrum disorder. Biol Psychiatry 2017;81(5):411-23. doi: 10.1016/j.biopsych.2016.08.024.

Rademacher S, Eickholt BJ. PTEN in autism and neurodevelopmental disorders. Cold Spring Harb Perspect Med 2019;1;9(11):a036780. doi: 10.1101/cshperspect.a036780.

Zhou J, Parada LF. PTEN signaling in autism spectrum disorders. Curr Opin Neurobiol 2012;22(5):873-9. doi: 10.1016/j.conb.2012.05.004.

Spinelli L, Black FM, Berg JN, Eickholt BJ, Leslie NR. Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes. J Med Genet 2015;52(2):128-34. doi: 10.1136/jmedgenet-2014-102803.

Feng C, Chen Y, Zhang Y, Yan Y, Yang M, Gui H, et al. PTEN regulates mitochondrial biogenesis via the AKT/GSK-3β/PGC-1α pathway in autism. Neuroscience 2021;15;465:85-94. doi: 10.1016/j.neuroscience.2021.04.010.

Gonzales J, Marchix J, Aymeric L, Le Berre-Scoul C, Zoppi J, Bordron P, et al. Fecal supernatant from adult with autism spectrum disorder alters digestive functions, intestinal epithelial barrier, and enteric nervous system. Microorganisms 2021;9(8):1723. doi: 10.3390/microorganisms9081723.

Bernier R, Golzio C, Xiong B, Stessman HA, Coe BP, Penn O, et al. Disruptive CHD8 mutations define a subtype of autism early in development. Cell 2014;158(2):263-76. doi: 10.1016/j.cell.2014.06.017.

Shteyer E, Edvardson S, Wynia-Smith SL, Pierri CL, Zangen T, Hashavya S, et al. Truncating mutation in the nitric oxide synthase 1 gene is associated with infantile achalasia. Gastroenterology 2015;148(3):533-6.e4. doi: 10.1053/j.gastro.2014.11.044.

Hosie S, Ellis M, Swaminathan M, Ramalhosa F, Seger GO, Balasuriya GK, et al. Gastrointestinal dysfunction in patients and mice expressing the autism-associated R451C mutation in neuroligin-3. Autism Res 2019;12(7):1043-56. doi: 10.1002/aur.2127.

Zheng Y, Verhoeff TA, Perez Pardo P, Garssen J, Kraneveld AD. The gut-brain axis in autism spectrum disorder: a focus on the metalloproteases ADAM10 and ADAM17. Int J Mol Sci 2020;22(1):118. doi:10.3390/ijms22010118.

Isolauri E, Salminen S, Ouwehand AC. Microbial-gut interactions in health and disease. Probiotics. Best Pract Res Clin Gastroenterol 2004;18(2):299-313. doi: 10.1016/j.bpg.2003.10.006.

Santocchi E, Guiducci L, Prosperi M, Calderoni S, Gaggini M, Apicella F, et al. Effects of probiotic supplementation on gastrointestinal, sensory and core symptoms in autism spectrum disorders: a randomized controlled trial. Front Psychiatry 2020;11:550593. doi: 10.3389/fpsyt.2020.550593.

Critchfield JW, van Hemert S, Ash M, Mulder L, Ashwood P. The potential role of probiotics in the management of childhood autism spectrum disorders. Gastroenterol Res Pract 2011;2011:161358. doi: 10.1155/2011/161358.

Wegh CAM, Geerlings SY, Knol J, Roeselers G, Belzer C. Postbiotics and their potential applications in early life nutrition and beyond. Int J Mol Sci 2019;20(19):4673. doi: 10.3390/ijms20194673.


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