Introduction: Differences in microbiota composition in children with autism spectrum disorder (ASD) compared to unaffected siblings and healthy controls have been reported in various studies. This study aims to systematically review the existing literature concerning the role of the gut microbiota in ASD. Methods: An extensive literature search was conducted using MEDLINE and EMBASE databases to identify studies (January 1966 through July 2019). Results: A total of 28 papers were included. The studies ranged from 12 to 104 participants who were aged between 2 and 18 years from various geographical areas. Majority of studies included faecal samples; however, 4 studies examined mucosal biopsies from different sites. The heterogeneity in ASD diagnostic methodology, gut site sampled and laboratory methods used made meta-analysis inappropriate. Species reported to be significantly higher in abundance in autistic children included Clostridium, Sutterella, Desulfovibrio and Lactobacillus. The findings are however inconsistent across studies. In addition, -potential confounding effects of antimicrobial use, gastrointestinal symptoms and diet on the gut microbiota are unclear due to generally poor assessment of these factors. Conclusion: It is clear that the gut microbiota is altered in ASD, although further exploration is needed on whether this is a cause or an effect of the condition.

Keywords:
Autism spectrum disorder, Gastrointestinal, Gut, Microbiota, Microbiome
1.
Rosenfeld CS. Microbiome Disturbances and Autism Spectrum Disorders.
Drug Metab Dispos
. 2015 Oct;43(10):1557–71.
2.
Centers for Disease Control and Prevention [Internet]. Data & Statistics on Autism Spectrum Disorder [cited Jan 2019]. Available from: https://www.cdc.gov/ncbddd/autism/data.html.
3.
Tordjman S, Somogyi E, Coulon N, Kermarrec S, Cohen D, Bronsard G, et al. Gene × Environment interactions in autism spectrum disorders: role of epigenetic mechanisms.
Front Psychiatry
. 2014 Aug;5:53.
4.
London EA. The environment as an etiologic factor in autism: a new direction for research.
Environ Health Perspect
. 2000 Jun;108(Suppl 3):401–4.
5.
Clemente JC, Ursell LK, Parfrey LW, Knight R. The impact of the gut microbiota on human health: an integrative view.
Cell
. 2012 Mar;148(6):1258–70.
6.
Thursby E, Juge N. Introduction to the human gut microbiota.
Biochem J
. 2017 May;474(11):1823–36.
7.
O’Hara AM, Shanahan F. The gut flora as a forgotten organ.
EMBO Rep
. 2006 Jul;7(7):688–93.
8.
Buie T, Campbell DB, Fuchs GJ 3rd, Furuta GT, Levy J, Vandewater J, et al. Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report.
Pediatrics
. 2010 Jan;125(Suppl 1):S1–18.
9.
McElhanon BO, McCracken C, Karpen S, Sharp WG. Gastrointestinal symptoms in autism spectrum disorder: a meta-analysis.
Pediatrics
. 2014 May;133(5):872–83.
10.
Frye RE, Slattery J, MacFabe DF, Allen-Vercoe E, Parker W, Rodakis J, et al. Approaches to studying and manipulating the enteric microbiome to improve autism symptoms.
Microb Ecol Health Dis
. 2015 May;26:26878.
11.
Gilbert JA, Krajmalnik-Brown R, Porazinska DL, Weiss SJ, Knight R. Toward effective probiotics for autism and other neurodevelopmental disorders.
Cell
. 2013 Dec;155(7):1446–8.
12.
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 Dec;155(7):1451–63.
13.
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 Jan;5(1):10.
14.
Wells GA, Shea B, O’connell D, Peterson J, Welch V, Losos M, et al. [Internet] The Newcastle-Ottawa Scale [NOS] for assessing the quality of nonrandomised studies in meta-analyses [cited April 2018]. Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.
15.
Plaza-Diaz J, Gomez-Fernandez A, Chueca N, Torre-Aguilar MJ, Gil A, Perez-Navero JL, et al. Autism Spectrum Disorder [ASD] with and without Mental Regression is Associated with Changes in the Fecal Microbiota. Nutrients 2019 Feb 5;11(2):e337.
16.
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 Jul;8(7):e68322.
17.
Kushak RI, Winter HS, Buie TM, Cox SB, Phillips CD, Ward NL. Analysis of the Duodenal Microbiome in Autistic Individuals: Association With Carbohydrate Digestion.
J Pediatr Gastroenterol Nutr
. 2017 May;64(5):e110–6.
18.
Luna RA, Oezguen N, Balderas M, Venkatachalam A, Runge JK, Versalovic J, et al. Distinct Microbiome-Neuroimmune Signatures Correlate With Functional Abdominal Pain in Children With Autism Spectrum Disorder.
Cell Mol Gastroenterol Hepatol
. 2016 Dec;3(2):218–30.
19.
Song Y, Liu C, Finegold SM. Real-time PCR quantitation of clostridia in feces of autistic children.
Appl Environ Microbiol
. 2004 Nov;70(11):6459–65.
20.
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 Feb;5(1):24.
21.
Williams BL, Hornig M, Parekh T, 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 Jan;3(1):e00261–11.
22.
Coretti L, Paparo L, Riccio MP, Amato F, Cuomo M, Natale A, et al. Gut Microbiota Features in Young Children With Autism Spectrum Disorders.
Front Microbiol
. 2018 Dec;9:3146.
23.
Liu S, Li E, Sun Z, Fu D, Duan G, Jiang M, et al. Altered gut microbiota and short chain fatty acids in Chinese children with autism spectrum disorder.
Sci Rep
. 2019 Jan;9(1):287.
24.
Ma B, Liang J, Dai M, Wang J, Luo J, Zhang Z, et al. Altered Gut Microbiota in Chinese Children With Autism Spectrum Disorders.
Front Cell Infect Microbiol
. 2019 Mar;9:40.
25.
Zhang M, Ma W, Zhang J, He Y, Wang J. Analysis of gut microbiota profiles and microbe-disease associations in children with autism spectrum disorders in China.
Sci Rep
. 2018 Sep;8(1):13981.
26.
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 Feb;17(1):26–38.
27.
Zhai Q, Cen S, Jiang J, Zhao J, Zhang H, Chen W. Disturbance of trace element and gut microbiota profiles as indicators of autism spectrum disorder: A pilot study of Chinese children.
Environ Res
. 2019 Apr;171:501–9.
28.
Wang M, Wan J, Rong H, He F, Wang H, Zhou J, et al. Alterations in Gut Glutamate Metabolism Associated with Changes in Gut Microbiota Composition in Children with Autism Spectrum Disorder.
mSystems
. 2019 Jan;4(1):e00321–18.
29.
Berding K, Donovan SM. Diet Can Impact Microbiota Composition in Children With Autism Spectrum Disorder.
Front Neurosci
. 2018 Jul;12:515.
30.
Inoue R, Sakaue Y, Sawai C, Sawai T, Ozeki M, Romero-Pérez GA, et al. A preliminary investigation on the relationship between gut microbiota and gene expressions in peripheral mononuclear cells of infants with autism spectrum disorders.
Biosci Biotechnol Biochem
. 2016 Dec;80(12):2450–8.
31.
Williams BL, Hornig M, Buie T, Bauman ML, Cho Paik M, Wick I, et al. Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances.
PLoS One
. 2011;6(9):e24585.
32.
Kang DW, Ilhan ZE, Isern NG, Hoyt DW, Howsmon DP, Shaffer M, et al. Differences in fecal microbial metabolites and microbiota of children with autism spectrum disorders.
Anaerobe
. 2018 Feb;49:121–31.
33.
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 May;70:354–68.
34.
Gondalia SV, Palombo EA, Knowles SR, Cox SB, Meyer D, Austin DW. Molecular characterisation of gastrointestinal microbiota of children with autism (with and without gastrointestinal dysfunction) and their neurotypical siblings.
Autism Res
. 2012 Dec;5(6):419–27.
35.
De Angelis M, Piccolo M, Vannini L, Siragusa S, De Giacomo A, Serrazzanetti DI, et al. Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified.
PLoS One
. 2013 Oct;8(10):e76993.
36.
Son JS, Zheng LJ, Rowehl LM, Tian X, Zhang Y, Zhu W, et al. Comparison of Fecal Microbiota in Children with Autism Spectrum Disorders and Neurotypical Siblings in the Simons Simplex Collection.
PLoS One
. 2015 Oct;10(10):e0137725.
37.
Pulikkan J, Maji A, Dhakan DB, Saxena R, Mohan B, Anto MM, et al. Gut Microbial Dysbiosis in Indian Children with Autism Spectrum Disorders.
Microb Ecol
. 2018 Nov;76(4):1102–14.
38.
Finegold SM, Dowd SE, Gontcharova V, Liu C, Henley KE, Wolcott RD, et al. Pyrosequencing study of fecal microflora of autistic and control children.
Anaerobe
. 2010 Aug;16(4):444–53.
39.
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 Jan;138:179–87.
40.
Wang L, Christophersen CT, Sorich MJ, Gerber JP, Angley MT, Conlon MA. Low relative abundances of the mucolytic bacterium Akkermansia muciniphila and Bifidobacterium spp. in feces of children with autism.
Appl Environ Microbiol
. 2011 Sep;77(18):6718–21.
41.
Wang L, Christophersen CT, Sorich MJ, Gerber JP, Angley MT, Conlon MA. Increased abundance of Sutterella spp. and Ruminococcus torques in feces of children with autism spectrum disorder.
Mol Autism
. 2013 Nov;4(1):42.
42.
Parracho HM, Bingham MO, Gibson GR, McCartney AL. Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children.
J Med Microbiol
. 2005 Oct;54(Pt 10):987–91.
43.
American Psychiatric Association.
Diagnostic and Statistical Manual of Mental Disorders
. 4th Edition, Text Revision. United States: DSM-IV-TR; 2000.
44.
American Psychiatric Association.
Diagnostic and Statistical Manual of Mental Disorders
, 5th Edition. DSM-5. United States; 2013.
45.
Lord C, Rutter M, Le Couteur A. Autism Diagnostic Interview-Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders.
J Autism Dev Disord
. 1994 Oct;24(5):659–85.
46.
Lord C, Risi S, Lambrecht L, Cook EH Jr, Leventhal BL, DiLavore PC, et al. The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism.
J Autism Dev Disord
. 2000 Jun;30(3):205–23.
47.
Schopler E, Reichler RJ, DeVellis RF, Daly K. Toward objective classification of childhood autism: Childhood Autism Rating Scale (CARS).
J Autism Dev Disord
. 1980 Mar;10(1):91–103.
48.
Kamio Y, Yukihiro R, Adachi J. Reliability and validity of the pervasive developmental disorder [PDD]-Autism society Japan rating scale [PARS]: a behavior checklist for adolescents and adults with PDDs.
Clin Psychiat
. 2006;48:485–505.
49.
Robins DL, Fein D, Barton ML, Green JA. The Modified Checklist for Autism in Toddlers: an initial study investigating the early detection of autism and pervasive developmental disorders.
J Autism Dev Disord
. 2001 Apr;31(2):131–44.
50.
Autism Researcg Institute [Internet]. Autism Treatment Evaluation checklist [ATEC] [cited September 2019]. Available from: https://www.autism.com/ind_atec.
51.
Cohen IL. Criterion-related validity of the PDD Behavior Inventory.
J Autism Dev Disord
. 2003 Feb;33(1):47–53.
52.
Juneja M, Mishra D, Russell PS, Gulati S, Deshmukh V, Tudu P, et al.; INCLEN Study Group. INCLEN Diagnostic Tool for Autism Spectrum Disorder (INDT-ASD): development and validation.
Indian Pediatr
. 2014 May;51(5):359–65.
53.
Mukherjee SB, Malhotra MK, Aneja S, Chakraborty S, Deshpande S. Diagnostic accuracy of Indian Scale for Assessment of Autism (ISAA) in chidren aged 2-9 years.
Indian Pediatr
. 2015 Mar;52(3):212–6.
54.
World Health Organisation [Internet]. The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines [cited September 2019]. Available from: https://apps.who.int/iris/handle/10665/37958.
55.
Dethlefsen L, Huse S, Sogin ML, Relman DA. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing.
PLoS Biol
. 2008 Nov;6(11):e280.
56.
DiLorenzo C, Rasquin A, Forbes D, Guiraldes E, Hyams J, Staiano A, et al. Childhood functional gastrointestinal disorders: child/adolescent. In: Drossman DA, editor.
Rome III: The Functional Gastrointestinal Disorders
. 3rd ed. McLean (VA): Degnon Associates, Inc; 2006. pp. 723–77.
57.
Koppen IJ, Nurko S, Saps M, Di Lorenzo C, Benninga MA. The pediatric Rome IV criteria: what’s new?
Expert Rev Gastroenterol Hepatol
. 2017 Mar;11(3):193–201.
58.
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 Mar;11(1):22.
59.
Chaidez V, Hansen RL, Hertz-Picciotto I. Gastrointestinal problems in children with autism, developmental delays or typical development.
J Autism Dev Disord
. 2014 May;44(5):1117–27.
60.
Singh RK, Chang HW, Yan D, Lee KM, Ucmak D, Wong K, et al. Influence of diet on the gut microbiome and implications for human health.
J Transl Med
. 2017 Apr;15(1):73.
61.
Makki K, Deehan EC, Walter J, Bäckhed F. The Impact of Dietary Fiber on Gut Microbiota in Host Health and Disease.
Cell Host Microbe
. 2018 Jun;23(6):705–15.
62.
Hiippala K, Kainulainen V, Kalliomäki M, Arkkila P, Satokari R. Mucosal Prevalence and Interactions with the Epithelium Indicate Commensalism of Sutterella spp.
Front Microbiol
. 2016 Oct;7:1706.
63.
Mukhopadhya I, Hansen R, Nicholl CE, Alhaidan YA, Thomson JM, Berry SH, et al. A comprehensive evaluation of colonic mucosal isolates of Sutterella wadsworthensis from inflammatory bowel disease.
PLoS One
. 2011;6(10):e27076.
64.
Finegold SM. Desulfovibrio species are potentially important in regressive autism.
Med Hypotheses
. 2011 Aug;77(2):270–4.
65.
Holzapfel WH, Haberer P, Geisen R, Björkroth J, Schillinger U. Taxonomy and important features of probiotic microorganisms in food and nutrition.
Am J Clin Nutr
. 2001 Feb;73(2 Suppl):365S–73S.
66.
MacFabe DF. Enteric short-chain fatty acids: microbial messengers of metabolism, mitochondria, and mind: implications in autism spectrum disorders.
Microb Ecol Health Dis
. 2015 May;26:28177.
67.
Ashwood 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 Jan;25(1):40–5.
68.
Goines PE, Ashwood P. Cytokine dysregulation in autism spectrum disorders (ASD): possible role of the environment.
Neurotoxicol Teratol
. 2013 Mar-Apr;36:67–81.
69.
Bolte ER. Autism and Clostridium tetani.
Med Hypotheses
. 1998 Aug;5(2):133–44.
70.
Sandler RH, Finegold SM, Bolte ER, Buchanan CP, Maxwell AP, Väisänen ML, et al. Short-term benefit from oral vancomycin treatment of regressive-onset autism.
J Child Neurol
. 2000 Jul;15(7):429–35.
71.
Nithianantharajah J, Balasuriya GK, Franks AE, Hill-Yardin EL. Using Animal Models to Study the Role of the Gut-Brain Axis in Autism.
Curr Dev Disord Rep
. 2017;4(2):28–36.
72.
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 Mar;37:197–206.
73.
Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, et al. Diversity of the human intestinal microbial flora.
Science
. 2005 Jun;308(5728):1635–8.
74.
Ranjan S, Nasser JA. Nutritional status of individuals with autism spectrum disorders: do we know enough?
Adv Nutr
. 2015 Jul;6(4):397–407.
75.
Sathe N, Andrews JC, McPheeters ML, Warren ZE. Nutritional and Dietary Interventions for Autism Spectrum Disorder: A Systematic Review.
Pediatrics
. 2017 Jun;139(6):e20170346.
76.
Scott KP, Gratz SW, Sheridan PO, Flint HJ, Duncan SH. The influence of diet on the gut microbiota.
Pharmacol Res
. 2013 Mar;69(1):52–60.
77.
David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, et al. Diet rapidly and reproducibly alters the human gut microbiome.
Nature
. 2014 Jan;505(7484):559–63.
78.
Niehus R, Lord C. Early medical history of children with autism spectrum disorders.
J Dev Behav Pediatr
. 2006 Apr;27(2 Suppl):S120–7.
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