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The Gut Microbiota and Dysbiosis in Autism Spectrum Disorders

  • Heather K. Hughes
  • Destanie Rose
  • Paul Ashwood
Pediatric Neurology (W Kaufmann, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Pediatric Neurology

Abstract

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.

Recent Findings

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.

Summary

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.

Keywords

Autism Microbiota Dysbiosis Dysregulation Neurodevelopment Behavior 

Notes

Acknowledgements

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.

References

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

  1. 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
  2. 2.
    Abrahams BS, Geschwind DH. Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet. 2008;9(5):341–55.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Raz R, Roberts AL, Lyall K, Hart JE, Just AC, Laden F, et al. Autism spectrum disorder and particulate matter air pollution before, during, and after pregnancy: a nested case-control analysis within the Nurses' health study II cohort. Environ Health Perspect. 2015;123(3):264–70.PubMedGoogle Scholar
  4. 4.
    Shelton JF, Geraghty EM, Tancredi DJ, Delwiche LD, Schmidt RJ, Ritz B, et al. Neurodevelopmental disorders and prenatal residential proximity to agricultural pesticides: the CHARGE study. Environ Health Perspect. 2014;122(10):1103–9.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Atladóttir HÓ, Henriksen TB, Schendel DE, Parner ET. Autism after infection, febrile episodes, and antibiotic use during pregnancy: an exploratory study. Pediatrics. 2012;130.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Onore C, Careaga M, Ashwood P. The role of immune dysfunction in the pathophysiology of autism. Brain Behav Immun. 2012;26(3):383–92.PubMedGoogle Scholar
  7. 7.
    McElhanon BO, McCracken C, Karpen S, Sharp WG. Gastrointestinal symptoms in autism spectrum disorder: a meta-analysis. Pediatrics. 2014;133(5):872–83.PubMedGoogle Scholar
  8. 8.
    Mead J, Ashwood P. Evidence supporting an altered immune response in ASD. Immunol Lett. 2015;163(1):49–55.PubMedGoogle Scholar
  9. 9.
    The Human Microbiome Project C. Structure, function and diversity of the healthy human microbiome. Nature. 2012;486:207.Google Scholar
  10. 10.
    RodrÍguez JM, Murphy K, Stanton C, Ross RP, Kober OI, Juge N, et al. The composition of the gut microbiota throughout life, with an emphasis on early life. Microb Ecol Health Dis. 2015;26(1):26050.PubMedGoogle Scholar
  11. 11.
    Blaser MJ, Falkow S. What are the consequences of the disappearing human microbiota? Nat Rev Microbiol. 2009;7(12):887–94.PubMedGoogle Scholar
  12. 12.
    Tamboli CP, Neut C, Desreumaux P, Colombel JF. Dysbiosis in inflammatory bowel disease. Gut. 2004;53(1):1–4.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. Cell. 2014;157(1):121–41.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science. 2012;336(6086):1268–73.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Round JL, Mazmanian SK. The gut microbiome shapes intestinal immune responses during health and disease. Nature reviews. Immunology 2009;9(5):313–323.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Chung H, Pamp SJ, Hill JA, Surana NK, Edelman SM, Troy EB, et al. Gut immune maturation depends on colonization with a host-specific microbiota. Cell. 2012;149(7):1578–93.PubMedPubMedCentralGoogle Scholar
  17. 17.
    El Aidy S, Hooiveld G, Tremaroli V, Backhed F, Kleerebezem M. The gut microbiota and mucosal homeostasis: colonized at birth or at adulthood, does it matter? Gut Microbes 2013;4(2):118–124.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Gensollen T, Iyer SS, Kasper DL, Blumberg RS. How colonization by microbiota in early life shapes the immune system. Science. 2016;352(6285):539–44.PubMedPubMedCentralGoogle Scholar
  19. 19.
    van de Wouw M, Schellekens H, Dinan TG, Cryan JF. Microbiota-gut-brain Axis: modulator of host metabolism and appetite. J Nutr. 2017;147(5):727–45.PubMedGoogle Scholar
  20. 20.
    Jandhyala SM, Talukdar R, Subramanyam C, Vuyyuru H, Sasikala M, Reddy DN. Role of the normal gut microbiota. World J Gastroenterol: WJG. 2015;21(29):8787–803.PubMedGoogle Scholar
  21. 21.
    Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012;13(10):701–12.PubMedGoogle Scholar
  22. 22.
    • Vuong HE, Yano JM, Fung TC, Hsiao EY. The microbiome and host behavior. Ann Rev Neurosci. 2017;40(1):21–49 Comprehensive review of the influence of microbiota on behavior in animal models. PubMedGoogle Scholar
  23. 23.
    Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu XN, et al. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol. 2004;558(Pt 1):263–75.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Neufeld KM, Kang N, Bienenstock J, Foster JA. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil. 2011;23(3):255–64 e119.PubMedGoogle Scholar
  25. 25.
    Diaz Heijtz R, Wang S, Anuar F, Qian Y, Bjorkholm B, Samuelsson A, et al. Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A. 2011;108(7):3047–52.PubMedGoogle Scholar
  26. 26.
    Clarke G, Grenham S, Scully P, Fitzgerald P, Moloney RD, Shanahan F, et al. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry. 2013;18(6):666–73.PubMedGoogle Scholar
  27. 27.
    Campos AC, Rocha NP, Nicoli JR, Vieira LQ, Teixeira MM, Teixeira AL. Absence of gut microbiota influences lipopolysaccharide-induced behavioral changes in mice. Behav Brain Res. 2016;312:186–94.PubMedGoogle Scholar
  28. 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
  29. 29.
    Savignac HM, Tramullas M, Kiely B, Dinan TG, Cryan JF. Bifidobacteria modulate cognitive processes in an anxious mouse strain. Behav Brain Res. 2015;287:59–72.PubMedGoogle Scholar
  30. 30.
    Liang S, Wang T, Hu X, Luo J, Li W, Wu X, et al. Administration of Lactobacillus helveticus NS8 improves behavioral, cognitive, and biochemical aberrations caused by chronic restraint stress. Neuroscience. 2015;310:561–77.PubMedGoogle Scholar
  31. 31.
    Emge JR, Huynh K, Miller EN, Kaur M, Reardon C, Barrett KE, et al. Modulation of the microbiota-gut-brain axis by probiotics in a murine model of inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol. 2016;310(11):G989–98.PubMedGoogle Scholar
  32. 32.
    O'Mahony SM, Marchesi JR, Scully P, Codling C, Ceolho AM, Quigley EM, et al. Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol Psychiatry. 2009;65(3):263–7.PubMedGoogle Scholar
  33. 33.
    Gareau MG, Wine E, Rodrigues DM, Cho JH, Whary MT, Philpott DJ, et al. Bacterial infection causes stress-induced memory dysfunction in mice. Gut. 2011;60(3):307–17.PubMedGoogle Scholar
  34. 34.
    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.PubMedPubMedCentralGoogle Scholar
  35. 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
  36. 36.
    Barrett E, Ross RP, O'Toole PW, Fitzgerald GF, Stanton C. Gamma-aminobutyric acid production by culturable bacteria from the human intestine. J Appl Microbiol. 2012;113(2):411–7.PubMedGoogle Scholar
  37. 37.
    Lyte M. Probiotics function mechanistically as delivery vehicles for neuroactive compounds: microbial endocrinology in the design and use of probiotics. BioEssays. 2011;33(8):574–81.PubMedGoogle Scholar
  38. 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
  39. 39.
    Kelly CJ, Zheng L, Campbell EL, Saeedi B, Scholz CC, Bayless AJ, et al. Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function. Cell Host Microbe. 2015;17(5):662–71.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Bruce-Keller AJ, Salbaum JM, Luo M. Blanchard et, Taylor CM, welsh DA, et al. obese-type gut microbiota induce neurobehavioral changes in the absence of obesity. Biol Psychiatry. 2015;77(7):607–15.PubMedGoogle Scholar
  41. 41.
    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.PubMedPubMedCentralGoogle Scholar
  42. 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. 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
  44. 44.
    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.PubMedPubMedCentralGoogle Scholar
  45. 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
  46. 46.
    Sandler RH, Finegold SM, Bolte ER, Buchanan CP, Maxwell AP, Vaisanen ML, et al. Short-term benefit from oral vancomycin treatment of regressive-onset autism. J Child Neurol. 2000;15(7):429–35.PubMedGoogle Scholar
  47. 47.
    Finegold SM, Molitoris D, Song Y, Liu C, Vaisanen ML, Bolte E, et al. Gastrointestinal microflora studies in late-onset autism. Clin Infect Dis. 2002;35(Suppl 1):S6–s16.PubMedGoogle Scholar
  48. 48.
    Song Y, Liu C, Finegold SM. Real-time PCR quantitation of clostridia in feces of autistic children. Appl Environ Microbiol. 2004;70(11):6459–65.PubMedPubMedCentralGoogle Scholar
  49. 49.
    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;54(Pt 10):987–91.PubMedGoogle Scholar
  50. 50.
    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;16(4):444–53.PubMedGoogle Scholar
  51. 51.
    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.PubMedPubMedCentralGoogle Scholar
  52. 52.
    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;77(18):6718–21.PubMedPubMedCentralGoogle Scholar
  53. 53.
    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.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Martirosian G, Ekiel A, Aptekorz M, Wiechula B, Kazek B, Jankowska-Steifer E, et al. Fecal lactoferrin and Clostridium spp. in stools of autistic children. Anaerobe. 2011;17(1):43–5.PubMedGoogle Scholar
  55. 55.
    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;5(6):419–27.PubMedGoogle Scholar
  56. 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. 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
  58. 58.
    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.PubMedGoogle Scholar
  59. 59.
    Shaw W. Increased urinary excretion of a 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), an abnormal phenylalanine metabolite of clostridia spp. in the gastrointestinal tract, in urine samples from patients with autism and schizophrenia. Nutr Neurosci. 2010;13(3):135–43.PubMedGoogle Scholar
  60. 60.
    Altieri L, Neri C, Sacco R, Curatolo P, Benvenuto A, Muratori F, et al. Urinary p-cresol is elevated in small children with severe autism spectrum disorder. Biomarkers: biochemical indicators of exposure, response, and susceptibility to chemicals. Biomarkers 2011;16(3):252–60.PubMedGoogle Scholar
  61. 61.
    Wang L, Christophersen CT, Sorich MJ, Gerber JP, Angley MT, Conlon MA. Elevated fecal short chain fatty acid and ammonia concentrations in children with autism spectrum disorder. Dig Dis Sci. 2012;57(8):2096–102.PubMedGoogle Scholar
  62. 62.
    Kaluzna-Czaplinska J, Blaszczyk S. The level of arabinitol in autistic children after probiotic therapy. Nutrition (Burbank, Los Angeles County, Calif) 2012;28(2):124–6.PubMedGoogle Scholar
  63. 63.
    Ming X, Stein TP, Barnes V, Rhodes N, Guo L. Metabolic perturbance in autism spectrum disorders: a metabolomics study. J Proteome Res. 2012;11(12):5856–62.PubMedGoogle Scholar
  64. 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. 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
  66. 66.
    Gabriele S, Sacco R, Persico AM. Blood serotonin levels in autism spectrum disorder: a systematic review and meta-analysis. Eur Neuropsychopharmacol. 2014;24(6):919–29.PubMedGoogle Scholar
  67. 67.
    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.PubMedGoogle Scholar
  68. 68.
    Gevi F, Zolla L, Gabriele S, Persico AM. Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism. Molecular Autism. 2016;7:47.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Xiong X, Liu D, Wang Y, Zeng T, Peng Y. Urinary 3-(3-Hydroxyphenyl)-3-hydroxypropionic acid, 3-Hydroxyphenylacetic acid, and 3-Hydroxyhippuric acid are elevated in children with autism Spectrum disorders. Biomed Res Int. 2016;2016:9485412.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Gabriele S, Sacco R, Altieri L, Neri C, Urbani A, Bravaccio C, et al. Slow intestinal transit contributes to elevate urinary p-cresol level in Italian autistic children. Autism Res. 2016;9(7):752–9.PubMedGoogle Scholar
  71. 71.
    Png CW, Linden SK, Gilshenan KS, Zoetendal EG, McSweeney CS, Sly LI, et al. Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria. Am J Gastroenterol. 2010;105(11):2420–8.PubMedGoogle Scholar
  72. 72.
    Lussu M, Noto A, Masili A, Rinaldi AC, Dessì A, De Angelis M, et al. The urinary 1H-NMR metabolomics profile of an italian autistic children population and their unaffected siblings. Autism Res. 2017;10(6):1058–66.PubMedGoogle Scholar
  73. 73.
    Kang D-W, 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;49:121–31.PubMedGoogle Scholar
  74. 74.
    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.PubMedPubMedCentralGoogle Scholar
  75. 75.
    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;10(10):e0137725.PubMedPubMedCentralGoogle Scholar
  76. 76.
    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.PubMedGoogle Scholar
  77. 77.
    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;64(5):e110–e6.PubMedGoogle Scholar
  78. 78.
    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.PubMedPubMedCentralGoogle Scholar
  79. 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
  80. 80.
    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;4.PubMedPubMedCentralGoogle Scholar
  81. 81.
    Carbonero F, Benefiel AC, Alizadeh-Ghamsari AH, Gaskins HR. Microbial pathways in colonic sulfur metabolism and links with health and disease. Front Physiol. 2012;3:448.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Ritz NL, Burnett BJ, Setty P, Reinhart KM, Wilson MR, Alcock J, et al. Sulfate-reducing bacteria impairs working memory in mice. Physiol Behav. 2016;157:281–7.PubMedGoogle Scholar
  83. 83.
    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. 2017;3(2):218–30.PubMedGoogle Scholar
  84. 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
  85. 85.
    Winter SE, Winter MG, Xavier MN, Thiennimitr P, Poon V, Keestra AM, et al. Host-derived nitrate boosts growth of E. coli in the inflamed gut. Science. 2013;339(6120):708–11.PubMedPubMedCentralGoogle Scholar
  86. 86.
    Rose D, Ashwood P. Potential cytokine biomarkers in autism spectrum disorders. Biomark Med. 2014;8(9):1171–81.PubMedGoogle Scholar
  87. 87.
    Cao X, Lin P, Jiang P, Li C. Characteristics of the gastrointestinal microbiome in children with autism spectrum disorder: a systematic review. Shanghai Arch Psychiatry. 2013;25(6):342–53.PubMedPubMedCentralGoogle Scholar
  88. 88.
    Hiergeist A, Glasner J, Reischl U, Gessner A. Analyses of intestinal microbiota: culture versus sequencing. ILAR J. 2015;56(2):228–40.PubMedGoogle Scholar
  89. 89.
    Cermak SA, Curtin C, Bandini LG. Food selectivity and sensory sensitivity in children with autism spectrum disorders. J Am Diet Assoc. 2010;110(2):238–46.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Partty A, Kalliomaki M, Wacklin P, Salminen S, Isolauri E. A possible link between early probiotic intervention and the risk of neuropsychiatric disorders later in childhood: a randomized trial. Pediatr Res. 2015;77(6):823–8.PubMedGoogle Scholar
  91. 91.
    Cui L, Morris A, Ghedin E. The human mycobiome in health and disease. Genome Med. 2013;5(7):63.PubMedPubMedCentralGoogle Scholar
  92. 92.
    Li Q, Wang C, Tang C, He Q, Li N, Li J. Dysbiosis of gut fungal microbiota is associated with mucosal inflammation in Crohn's disease. J Clin Gastroenterol. 2014;48(6):513–23.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Gerard R, Sendid B, Colombel JF, Poulain D, Jouault T. An immunological link between Candida albicans colonization and Crohn's disease. Crit Rev Microbiol. 2015;41(2):135–9.PubMedGoogle Scholar
  94. 94.
    Harnett J, Myers SP, Rolfe M. Significantly higher faecal counts of the yeasts candida and saccharomyces identified in people with coeliac disease. Gut Pathogens. 2017;9:26.PubMedPubMedCentralGoogle Scholar
  95. 95.
    Erb Downward JR, Falkowski NR, Mason KL, Muraglia R, Huffnagle GB. Modulation of post-antibiotic bacterial community reassembly and host response by Candida albicans. Sci Rep. 2013;3:2191.PubMedPubMedCentralGoogle Scholar
  96. 96.
    Kantarcioglu AS, Kiraz N, Aydin A. Microbiota-gut-brain Axis: yeast species isolated from stool samples of children with suspected or diagnosed autism Spectrum disorders and in vitro susceptibility against nystatin and fluconazole. Mycopathologia. 2016;181(1–2):1–7.PubMedGoogle Scholar
  97. 97.
    Iovene MR, Bombace F, Maresca R, Sapone A, Iardino P, Picardi A, et al. Intestinal Dysbiosis and yeast isolation in stool of subjects with autism Spectrum disorders. Mycopathologia. 2017;182(3–4):349–63.PubMedGoogle Scholar
  98. 98.
    Sigmundsdottir G, Larsson L, Wiebe T, Bjorklund LJ, Christensson B. Clinical experience of urine D-arabinitol/L-arabinitol ratio in the early diagnosis of invasive candidiasis in paediatric high risk populations. Scand J Infect Dis. 2007;39(2):146–51.PubMedGoogle Scholar
  99. 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. 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. 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. 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
  103. 103.
    Agus A, Planchais J, Sokol H. Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe. 2018;23(6):716–24.PubMedGoogle Scholar
  104. 104.
    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.PubMedPubMedCentralGoogle Scholar
  105. 105.
    Diémé B, Mavel S, Blasco H, Tripi G, Bonnet-Brilhault F, Malvy J, et al. Metabolomics study of urine in autism Spectrum disorders using a multiplatform analytical methodology. J Proteome Res. 2015;14(12):5273–82.PubMedGoogle Scholar
  106. 106.
    Guillemin GJ, Smith DG, Smythe GA, Armati PJ, Brew BJ. Expression of the kynurenine pathway enzymes in human microglia and macrophages. Adv Exp Med Biol. 2003;527:105–12.PubMedGoogle Scholar
  107. 107.
    Li Z, Chalazonitis A. Huang Y-y, Mann JJ, Margolis KG, Yang QM, et al. essential roles of enteric neuronal serotonin in gastrointestinal motility and the development/survival of enteric dopaminergic neurons. J Neurosci. 2011;31(24):8998–9009.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Ruddick JP, Evans AK, Nutt DJ, Lightman SL, Rook GA, Lowry CA. Tryptophan metabolism in the central nervous system: medical implications. Expert Rev Mol Med. 2006;8(20):1–27.PubMedGoogle Scholar
  109. 109.
    Miceli S, Negwer M, van Eijs F, Kalkhoven C, van Lierop I, Homberg J, et al. High serotonin levels during brain development alter the structural input-output connectivity of neural networks in the rat somatosensory layer IV. Front Cell Neurosci. 2013;7:88.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Bonaz B, Bazin T, Pellissier S. The Vagus nerve at the Interface of the microbiota-gut-brain Axis. Front Neurosci. 2018;12:49.PubMedPubMedCentralGoogle Scholar
  111. 111.
    Bercik P, Park AJ, Sinclair D, Khoshdel A, Lu J, Huang X, et al. The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut–brain communication. Neurogastroenterol Motil. 2011;23(12):1132–9.PubMedPubMedCentralGoogle Scholar
  112. 112.
    Bercik P, Denou E, Collins J, Jackson W, Lu J, Jury J, et al. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology. 2011;141(2):599–609 e1–3.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018
corrected publication September/2018

Authors and Affiliations

  • Heather K. Hughes
    • 1
    • 2
  • Destanie Rose
    • 1
    • 2
  • Paul Ashwood
    • 1
    • 2
  1. 1.Department of Medical Microbiology and ImmunologyUC DavisSacramentoUSA
  2. 2.The M.I.N.D. InstituteUniversity of California at DavisDavisUSA

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