The Gut Microbiota and Dysbiosis in Autism Spectrum Disorders
Purpose of Review
There is a growing body of evidence indicating the gut microbiota influence neurodevelopment and behavior. The purposes of this review are to provide an overview of studies analyzing the microbiota and their metabolites in autism spectrum disorders (ASD) and to discuss the possible mechanisms of action involved in microbial influence on the brain and behavior.
The microbiota-gut-brain (MGB) axis has been extensively studied in animal models, and it is clear that alterations in the composition of microbiota alter neurological and behavioral outcomes. However, findings in human studies are less abundant. Although there are several studies so far showing altered microbiota (dysbiosis) in ASD, the results are heterogeneous and often contradictory. Intervention studies such as fecal microbiota transplant therapies show promise and lend credence to the involvement of the microbiota in ASD.
A role for the microbiota in ASD is likely; however, further studies elucidating microbial or metabolomic signatures and mechanisms of action are needed. Future research should focus on intervention studies that can identify specific metabolites and immune mediators that improve with treatment to help identify etiologies and pathological mechanisms of ASD.
KeywordsAutism Microbiota Dysbiosis Dysregulation Neurodevelopment Behavior
Investigators were funded by the NIEHS Children’s Center grant (P01 ES011269), US EPA STAR program grant (R833292 and R829388), NIEHS CHARGE study (R01ES015359), NICHD (HD086669, HD090214 and U54 HD079125), Autism Research Institute, Autism Speaks Foundation, The Boler Company Foundation, NARSAD Foundation and the Johnson Foundation. This material is based upon work supported by the National Science Foundation Graduate Research Fellowship under Grant No. 1650042.
Compliance with Ethical Standards
Conflict of Interest
Heather K. Hughes, Destanie Rose, and Paul Ashwood each declare no potential conflicts of interest.
Human and Animal Rights
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.Baio J, Wiggins L, Christensen DL, Maenner MJ, Daniels J, Warren Z, et al. Prevalence of autism Spectrum disorder among children aged 8 years - autism and developmental disabilities monitoring network, 11 sites, United States, 2014. MMWR Surveill Summ. 2018;67(6):1–23.PubMedPubMedCentralGoogle Scholar
- 9.The Human Microbiome Project C. Structure, function and diversity of the healthy human microbiome. Nature. 2012;486:207.Google Scholar
- 28.Matthews DM, Jenks SM. Ingestion of Mycobacterium vaccae decreases anxiety-related behavior and improves learning in mice. Behav Process. 2013;96:27–35.Google Scholar
- 35.• Yano JM, Yu K, Donaldson GP, Shastri GG, Ann P, Ma L, et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell. 2015;161(2):264–76 Elegant study showing that serotonin production by the enterochromaffin cells in the gut is significantly influenced by spore-forming gut microbiota. PubMedPubMedCentralGoogle Scholar
- 38.•• 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 Study shows the influence of gut microbiota on the integrity of the blood-brain barrier, and found that mono-colonization with short-chain fatty acid producing bacteria could decrease blood-brain barrier permeability. PubMedPubMedCentralGoogle Scholar
- 42.• 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 Choi et al., 2016 identified the role of IL-17 in a maternal activation model of ASD. This follow up study study found that maternal IL-17 production was dependent on the composition of maternal microbiota. PubMedPubMedCentralGoogle Scholar
- 43.•• 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 Important study identifying the role of maternal IL-17 in abnormal cortical development in the offspring of a maternal activation model of autism. PubMedPubMedCentralGoogle Scholar
- 45.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. In: Brain Behav Immun; 2018.Google Scholar
- 56.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;3(1).Google Scholar
- 57.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. Behavior, and Immunity. 2018;70:354–68.Google Scholar
- 64.De Angelis M, Piccolo M, Vannini L, Siragusa S, De Giacomo A, Serrazzanetti DI. Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS One 2013;8.Google Scholar
- 65.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 : biochemical indicators of exposure, response, and susceptibility to chemicals. Biomarkers 2014;19(6):463–70.PubMedGoogle Scholar
- 79.• Kang D-W, 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 Pilot study of 18 children with ASD showed significant and persistent improvements in GI symptoms and ASD-relevant behaviors, with increases in Bifidobacterium , Prevotella and Desulfovibrio. PubMedPubMedCentralGoogle Scholar
- 84.Spees AM, Wangdi T, Lopez CA, Kingsbury DD, Xavier MN, Winter SE, et al. Streptomycin-induced inflammation enhances Escherichia coli gut colonization through nitrate respiration. MBio. 2013;4(4).Google Scholar
- 99.Vernocchi P, Del Chierico F, Putignani L. Gut microbiota profiling: metabolomics based approach to unravel compounds affecting human health. Front Microbiol. 1144;7:2016.Google Scholar
- 100.Shultz SR, MacFabe DF, Ossenkopp KP, Scratch S, Whelan J, Taylor R, et al. Intracerebroventricular injection of propionic acid, an enteric bacterial metabolic end-product, impairs social behavior in the rat: implications for an animal model of autism. Neuropharmacology. 2008;54(6):901–11.PubMedGoogle Scholar
- 101.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.PubMedGoogle Scholar
- 102.•• Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, de Roos P, et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. 2013;504(7480):451–5 Important study showing that short-chain fatty acids produced by commensal microbiota act as histone deacetylase inhibitors, promoting expression of Foxp3 and expansion of peripheral regulatory T cells. PubMedPubMedCentralGoogle Scholar