Altered Gut Microbiome in Autism Spectrum Disorder: Potential Mechanism and Implications for Clinical Intervention

Kuokuo Li1, Zhengmao Hu1, Jianjun Ou2, Kun Xia1

1Center for Medical Genetics and School of Life Sciences, Central South University, Changsha, Hunan, China

2Department of Psychiatry and Mental Health Institute of the Second Xiangya Hospital, Central South University, Changsha, Hunan, China

Received July 18, 2018; Accepted January 2, 2019


Autism spectrum disorder is a heterogeneous neurodevelopmental disorder with an increased prevalence around the world over the past two decades. Remarkably, a large number of individuals with ASD have gastrointestinal disorders. Recent studies demonstrate that the endogenous gut microbiota has a close relationship with ASD according to the analyses of human host intestinal microbial composition and animal model studies. Here, we review the reports of microbial dysbiosis in ASD, and then discuss the recent evidence of biological interactions among microbiota, metabolism, immunity, neurodevelopment, and behaviors. We also describe the role of the gut microbiome in the link between ASD and environmental risk factors. Finally, we suggest adjuvant treatments to consider in attempts to correct autistic behaviors.


Gut microbiome; autism spectrum disorder; clinical interventions

Copyright © 2019 by Global Clinical and Translational Research

How to cite this article:

Li K, Hu Z, Ou J, Xia K. Altered gut microbiome in Autism Spectrum Disorder: potential mechanism and implications for clinical intervention. Glob Clin Transl Res. 2019; 1(1):45-52. DOI:10.36316/gcatr.01.0006.


1.     Autism and Developmental Disabilities Monitoring Network Surveillance Year 2008 Principal Investigators; Centers for Disease Control and Prevention. Prevalence of autism spectrum disorders--Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2008. MMWR Surveill Summ. 2012; 61(3):1-19.

2.     Blumberg SJ, Bramlett MD, Kogan MD, Schieve LA, Jones JR, Lu MC. Changes in prevalence of parent-reported autism spectrum disorder in school-aged U.S. children: 2007 to 2011-2012. Natl Health Stat Report. 2013(65):1-11.

3.     Kim YS, Leventhal BL, Koh YJ, Fombonne E, Laska E, Lim EC, et al. Prevalence of autism spectrum disorders in a total population sample. Am J Psychiatry. 2011; 168(9):904-12.

4.     Lavelle TA, Weinstein MC, Newhouse JP, Munir K, Kuhlthau KA, Prosser LA. Economic burden of childhood autism spectrum disorders. Pediatrics. 2014; 133(3): e520-9.

5.     Baxter AJ, Brugha TS, Erskine HE, Scheurer RW, Vos T, Scott JG. The epidemiology and global burden of autism spectrum disorders. Psychol Med. 2015; 45 (3):601-13.

6.     Bercum FM, Rodgers KM, Benison AM, Smith ZZ, Taylor J, Kornreich E, et al. Maternal stress combined with terbutaline leads to comorbid autistic-like behavior and epilepsy in a rat model. J Neurosci. 2015; 35(48):15894-902.

7.     Krakowiak P, Goodlin-Jones B, Hertz-Picciotto I, Croen LA, Hansen RL. Sleep problems in children with autism spectrum disorders, developmental delays, and typical development: a population-based study. J Sleep Res. 2008; 17(2): 197-206.

8.     Pellock JM. Understanding co-morbidities affecting children with epilepsy. Neurology. 2004; 62(5 Suppl 2): S17-23.

9.     Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman CM, Reichenberg A. The familial risk of autism. JAMA. 2014; 311(17):1770-7.

10.   Colvert E, Tick B, McEwen F, Stewart C, Curran SR, Woodhouse E, et al. Heritability of autism spectrum disorder in a UK population-based twin sample. JAMA Psychiatry. 2015; 72(5):415-23.

11.   Ou J, Liu R, Shen Y, Xia K, Zhao J. An overview on genetic and environmental risk of autism spectrum disorder. Glob Clin Transl Res 2019; 1(1):11-21

12.   Chaidez V, Hansen RL, Hertz-Picciotto I. Gastrointestinal problems in children with autism, developmental delays or typical development. J Autism Dev Disord. 2014; 44(5): 1117-27.

13.   Jyonouchi H, Geng L, Ruby A, Reddy C, Zimmerman-Bier B. Evaluation of an association between gastrointestinal symptoms and cytokine production against common dietary proteins in children with autism spectrum disorders. J Pediatr. 2005; 146(5): 605 -10.

14.   McElhanon BO, McCracken C, Karpen S, Sharp WG. Gastrointestinal symptoms in autism spectrum disorder: a meta-analysis. Pediatrics. 2014; 133(5): 872-83.

15.   Benach JL, Li E, McGovern MM. A microbial association with autism. MBio. 2012; 3(1): e00019-12.

16.   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.

17.   Maynard CL, Elson CO, Hatton RD, Weaver CT. Reciprocal interactions of the intestinal microbiota and immune system. Nature. 2012; 489(7415):231-41.

18.   Tremaroli V, Backhed F. Functional interactions between the gut microbiota and host metabolism. Nature. 2012; 489(7415):242-9.

19.   Braniste V, Al-Asmakh M, Kowal C, Anuar F, Abbaspour A, Toth M, et al. The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med. 2014; 6(263): 263ra158.

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; 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 inte-stinal biopsy samples from children with autism and gas-trointestinal disturbances. MBio. 2012; 3(1): e00261-11.

22.   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.

23.   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.

24.   Yap IK, Angley M, Veselkov KA, Holmes E, Lindon JC, Nicholson JK. Urinary metabolic phenotyping differentiates children with autism from their unaffected siblings and age-matched controls. J Proteome Res. 2010; 9(6): 2996-3004.

25.   Wang H, Liang S, Wang M, Gao J, Sun C, Wang J, et al. Potential serum biomarkers from a metabolomics study of autism. J Psychiatry Neurosci. 2016; 41(1):27-37.

26.   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. Bio-markers. 2014; 19(6):463-70.

27.   Matsumoto M, Kibe R, Ooga T, Aiba Y, Kurihara S, Sawaki E, et al. Impact of intestinal microbiota on intestinal luminal metabolome. Sci Rep. 2012; 2:233.

28.   Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA, Peters EC, et al. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci U S A. 2009; 106(10): 3698-703.

29.   Perry RJ, Peng L, Barry NA, Cline GW, Zhang D, Cardone RL, et al. Acetate mediates a microbiome-brain-beta-cell axis to promote metabolic syndrome. Nature. 2016; 534(7606): 213-7.

30.   Zhang C, Zhang M, Wang S, Han R, Cao Y, Hua W, et al. Interactions between gut microbiota, host genetics and diet relevant to development of metabolic syndromes in mice. ISME J. 2010; 4(2):232-41.

31.   Org E, Parks BW, Joo JW, Emert B, Schwartzman W, Kang EY, et al. Genetic and environmental control of host-gut microbiota interactions. Genome Res. 2015; 25(10):1558-69.

32.   Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A. 2013; 110 (22):9066-71.

33.   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.

34.   Brown AS, Sourander A, Hinkka-Yli-Salomaki S, McKeague IW, Sundvall J, Surcel HM. Elevated maternal C-reactive protein and autism in a national birth cohort. Mol Psychiatry. 2014; 19(2):259-64.

35.   Estes ML, McAllister AK. Immune mediators in the brain and peripheral tissues in autism spectrum disorder. Nat Rev Neurosci. 2015; 16(8):469-86.

36.   McDougle CJ, Landino SM, Vahabzadeh A, O'Rourke J, Zurcher NR, Finger BC, et al. Toward an immune-mediated subtype of autism spectrum disorder. Brain Res. 2015; 1617:72-92.

37.   Patterson PH. Immune involvement in schizophrenia and autism: etiology, pathology and animal models. Behav Brain Res. 2009; 204(2):313-21.

38.   Estes ML, McAllister AK. Maternal immune activation: Implications for neuropsychiatric disorders. Science. 2016; 353(6301):772-7.

39.   Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005; 57(1): 67-81.

40.   Masi A, Quintana DS, Glozier N, Lloyd AR, Hickie IB, Guastella AJ. Cytokine aberrations in autism spectrum disorder: a systematic review and meta-analysis. Mol Psychiatry. 2015; 20(4):440-6.

41.   El-Ansary A, Al-Ayadhi L. GABAergic/glutamatergic imbalance relative to excessive neuroinflammation in autism spectrum disorders. J Neuroinflammation. 2014; 11:189.

42.   Xu N, Li X, Zhong Y. Inflammatory cytokines: potential bio-markers of immunologic dysfunction in autism spectrum disorders. Mediators Inflamm. 2015; 2015:531518.

43.   Goines PE, Croen LA, Braunschweig D, Yoshida CK, Grether J, Hansen R, et al. Increased midgestational IFN-gamma, IL-4 and IL-5 in women bearing a child with autism: A case-control study. Molecular Autism. 2011; 2:13.

44.   Thaiss CA, Zmora N, Levy M, Elinav E. The microbiome and innate immunity. Nature. 2016; 535 (7610):65-74.

45.   Hsiao EY, McBride SW, Chow J, Mazmanian SK, Patterson PH. Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proc Natl Acad Sci U S A. 2012; 109(31):12776-81.

46.   Malkova NV, Yu CZ, Hsiao EY, Moore MJ, Patterson PH. Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain Behav Immun. 2012; 26(4):607-16.

47.   Shin Yim Y, Park A, Berrios J, Lafourcade M, Pascual LM, Soares N, et al. Reversing behavioral abnormalities in mice exposed to maternal inflammation. Nature. 2017; 549 (7673):482-7.

48.   Wu HJ, Ivanov, II, Darce J, Hattori K, Shima T, Umesaki Y, et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity.2010; 32(6):815-27.

49.   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.

50.   Round JL, Lee SM, Li J, Tran G, Jabri B, Chatila TA, et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science. 2011; 332 (6032):974-7.

51.   Ivanov, II, Frutos Rde L, Manel N, Yoshinaga K, Rifkin DB, Sartor RB, and et al. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe.2008; 4(4):337-49.

52.   Courchesne E, Mouton PR, Calhoun ME, Semendeferi K, Ahrens-Barbeau C, Hallet MJ, et al. Neuron number and size in prefrontal cortex of children with autism. JAMA. 2011; 306(18):2001-10.

53.   Hazlett HC, Gu H, Munsell BC, Kim SH, Styner M, Wolff JJ, et al. Early brain development in infants at high risk for autism spectrum disorder. Nature. 2017; 542(7641):348-51.

54.   Le Belle JE, Sperry J, Ngo A, Ghochani Y, Laks DR, Lopez-Aranda M, et al. Maternal inflammation contributes to brain overgrowth and autism-associated behaviors through altered redox signaling in stem and progenitor cells. Stem Cell Reports. 2014; 3(5):725-34.

55.   Oskvig DB, Elkahloun AG, Johnson KR, Phillips TM, Herkenham M. Maternal immune activation by LPS selectively alters specific gene expression profiles of interneuron migration and oxidative stress in the fetus without triggering a fetal immune response. Brain Behav Immun. 2012; 26(4): 623-34.

56.   Ogbonnaya ES, Clarke G, Shanahan F, Dinan TG, Cryan JF, O'Leary OF. Adult Hippocampal Neurogenesis is regulated by the microbiome. Biol Psychiatry. 2015; 78(4): e7-9.

57.   Edmonson C, Ziats MN, Rennert OM. Altered glial marker expression in autistic post-mortem prefrontal cortex and cerebellum. Molecular Autism. 2014; 5(1):3.

58.   Suzuki K, Sugihara G, Ouchi Y, Nakamura K, Futatsubashi M, Takebayashi K, et al. Microglial activation in young adults with autism spectrum disorder. JAMA Psychiatry. 2013; 70(1):49-58.

59.   Erny D, Hrabe de Angelis AL, Jaitin D, Wieghofer P, Staszewski O, David E, et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci. 2015; 18(7):965-77.

60.   Tochitani S, Ikeno T, Ito T, Sakurai A, Yamauchi T, Matsuzaki H. Administration of non-absorbable antibiotics to pregnant mice to perturb the maternal gut microbiota is associated with alterations in offspring behavior. PLoS One. 2016; 11 (1): e 0138293.

61.   Degroote S, Hunting DJ, Baccarelli AA, Takser L. Maternal gut and fetal brain connection: increased anxiety and reduced social interactions in Wistar rat offspring following periconceptional antibiotic exposure. Prog Neuropsy-chopharmacol Biol Psychiatry. 2016; 71:76-82.

62.   Dominguez-Bello MG, Costello EK, Contreras M, Magris M, Hidalgo G, Fierer N, and et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A. 2010; 107 (26):11971-5.

63.   Biasucci G, Benenati B, Morelli L, Bessi E, Boehm G. Cesarean delivery may affect the early biodiversity of intestinal bacteria. J Nutr. 2008; 138(9):1796S-800S.

64.   Magne F, Puchi Silva A, Carvajal B, Gotteland M. The elevated rate of cesarean section and its contribution to non-communicable chronic diseases in Latin America: the growing involvement of the microbiota. Front Pediatr. 2017; 5:192.

65.   Curran EA, Dalman C, Kearney PM, Kenny LC, Cryan JF, Dinan TG, et al. Association between obstetric modes of delivery and autism spectrum disorder: a population-based sibling design study. JAMA Psychiatry. 2015; 72(9):935-42.

66.   Glasson EJ, Bower C, Petterson B, de Klerk N, Chaney G, Hallmayer JF. Perinatal factors and the development of autism: a population study. Arch Gen Psychiatry. 2004; 61(6):618-27.

67.   Dominguez-Bello MG, De Jesus-Laboy KM, Shen N, Cox LM, Amir A, Gonzalez A, et al. Partial restoration of the microbiota of cesarean-born infants via virginal microbial transfer. Nat Med. 2016; 22(3):250-3.

68.   Bronson SL, Bale TL. Prenatal stress-induced increases in placental inflammation and offspring hyperactivity are male-specific and ameliorated by maternal anti-inflammatory treatment. Endocrinology. 2014; 155(7):2635-46.

69.   Jasarevic E, Howerton CL, Howard CD, Bale TL. Alterations in the vaginal microbiome by maternal stress are associated with metabolic reprogramming of the offspring gut and brain. Endocrinology. 2015; 156(9):3265-76.

70.   Golubeva AV, Crampton S, Desbonnet L, Edge D, O'Sullivan O, Lomasney KW, et al. Prenatal stress-induced alterations in major physiological systems correlate with gut microbiota composition in adulthood. Psychoneuroendocrino-logy. 2015; 60:58-74.

71.   Lee BK, Magnusson C, Gardner RM, Blomstrom A, Newschaffer CJ, Burstyn I, et al. Maternal hospitalization with infection during pregnancy and risk of autism spectrum disorders. Brain Behav Immun. 2015; 44:100-5.

72.   Jiang HY, Xu LL, Shao L, Xia RM, Yu ZH, Ling ZX, et al. Maternal infection during pregnancy and risk of autism spectrum disorders: A systematic review and meta-analysis. Brain Behav Immun. 2016; 58: 165-72.

73.   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.

74.   Pearson BL, Simon JM, McCoy ES, Salazar G, Fragola G, Zylka MJ. Identification of chemicals that mimic transcriptional changes associated with autism, brain aging and neuro-degeneration. Nat Commun. 2016; 7:11173.

75.   Tran NQV, Miyake K. Neurodevelopmental disorders and environmental toxicants: epigenetics as an underlying mechanism. Int J Genomics. 2017; 2017:7526592.

76.   Singh K, Connors SL, Macklin EA, Smith KD, Fahey JW, Talalay P, et al. Sulforaphane treatment of autism spectrum disorder (ASD). Proc Natl Acad Sci U S A. 2014; 111 (43):15550-5.

77.   Accordino RE, Kidd C, Politte LC, Henry CA, McDougle CJ. Psychopharmacological interventions in autism spectrum disorder. Expert Opin Pharmacother. 2016; 17(7):937-52.

78.   Politte LC, Henry CA, McDougle CJ. Psychopharmacological interventions in autism spectrum disorder. Harv Rev Psychiatry. 2014; 22(2):76-92.

79.   Penagarikano O, Abrahams BS, Herman EI, Winden KD, Gdalyahu A, Dong H, et al. Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core auti-smrelated deficits. Cell. 2011; 147 (1): 235-46.

80.   McDougle CJ, Stigler KA, Erickson CA, Posey DJ. Atypical antipsychotics in children and adolescents with autistic and other pervasive developmental disorders. J Clin Psychiatry. 2008; 69 Suppl 4:15-20.

81.   McDougle CJ, Scahill L, McCracken JT, Aman MG, Tierney E, Arnold LE, et al. Research units on pediatric psychopharmacology (RUPP) autism network. Background and rati-onale for an initial controlled study of risperidone. Child Adolesc Psychiatr Clin N Am. 2000; 9(1):201-24.

82.   Urbano M, Okwara L, Manser P, Hartmann K, Herndon A, Deutsch SI. A trial of d-cycloserine to treat stereotypies in older adolescents and young adults with autism spectrum disorder. Clin Neuropharmacol. 2014; 37(3):69-72.

83.   Kwak MK, Kensler TW. Targeting NRF2 signaling for cancer chemoprevention. Toxicol Appl Pharmacol. 2010; 244 (1):66-76.

84.   Penagarikano O, Lazaro MT, Lu XH, Gordon A, Dong H, Lam HA, et al. Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism. Sci Transl Med. 2015; 7 (271):271ra8.

85.   Guastella AJ, Hickie IB. Oxytocin treatment, circuitry, and autism: a critical review of the literature placing oxytocin into the autism context. Biol Psychiatry.2016; 79(3):234-42.

86.   Stoop R. Neuromodulation by oxytocin and vasopressin. Neuron. 2012; 76(1):142-59.

87.   Buffington SA, Di Prisco GV, Auchtung TA, Ajami NJ, Petr-osino JF, Costa-Mattioli M. Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring. Cell. 2016; 165(7):1762-75.

88.   Rossen NG, MacDonald JK, de Vries EM, D'Haens GR, de Vos WM, Zoetendal EG, et al. Fecal microbiota transplantation as novel therapy in gastroenterology: A systematic review. World J Gastroenterol. 2015; 21(17):5359-71.

89.   Li Q, Han Y, Dy ABC, Hagerman RJ. The Gut micro-biota and autism spectrum disorders. Front Cell Neurosci. 2017; 11: 120.

90.   Kelly CR, Kahn S, Kashyap P, Laine L, Rubin D, Atreja A, et al. Update on fecal microbiota transplantation 2015: Indi-cations, Methodologies, Mechanisms, and Outlook. Gastro-enterology. 2015; 149(1):223-37.

91.   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.

92.   Scahill L, Jeon S, Boorin SJ, McDougle CJ, Aman MG, Dziura J, et al. Weight gain and metabolic consequences of risperidone in young children with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry. 2016; 55(5):415-23.

93.   van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013; 368 (5): 407-15.

94.   Youngster I, Sauk J, Pindar C, Wilson RG, Kaplan JL, Smith MB, et al. Fecal microbiota transplant for relapsing Clostridium difficile infection using a frozen inoculum from unrelated donors: a randomized, open-label, controlled pilot study. Clin Infect Dis. 2014; 58(11):1515-22.

95.   Kelly CR, Ihunnah C, Fischer M, Khoruts A, Surawicz C, Afzali A, et al. Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am J Gastroenterol. 2014; 109(7):1065-71.

96.   Hourigan SK, Oliva-Hemker M. Fecal microbiota transplantation in children: a brief review. Pediatr Res. 2016; 80 (1):2-6.