1887

Abstract

The human gut microbiota is currently seen as an important factor that can promote autism spectrum disorder (ASD) development in children.

This study aimed to detect differences in the taxonomic composition and content of bacterial genes encoding key enzymes involved in the metabolism of neuroactive biomarker compounds in the metagenomes of gut microbiota of children with ASD and neurotypical children.

A whole metagenome sequencing approach was used to obtain metagenomic data on faecal specimens of 36 children with ASD and 21 healthy neurotypical children of 3–5 years old. Taxonomic analysis was conducted using MetaPhlAn2. The developed bioinformatics algorithm and created catalogue of the orthologues were applied to identify bacterial genes of neuroactive compounds in the metagenomes. For the identification of metagenomic signatures of children with ASD, Wilcoxon's test and adjustment for multiple comparisons were used.

Statistically significant differences with decreases in average abundance in the microbiota of ASD children were found for the genera and and species , , , , and . Average relative abundances of the detected genes and neurometabolic signature approach did not reveal many significant differences in the metagenomes of the groups that were compared. We noted decreases in the abundance of genes linked to production of GABA, melatonine and butyric acid in the ASD metagenomes.

For the first time, the neurometabolic signature of the gut microbiota of young children with ASD is presented. The data can help to provide a comparative assessment of the transcriptional and metabolomic activity of the identified genes.

Funding
This study was supported by the:
  • Denis V. Rebrikov , Russian Science Foundation , (Award 17-15-01488)
Loading

Article metrics loading...

/content/journal/jmm/10.1099/jmm.0.001178
2020-03-26
2020-03-31
Loading full text...

Full text loading...

References

  1. Brown JM, Hazen SL. The gut microbial endocrine organ: bacterially derived signals driving cardiometabolic diseases. Annu Rev Med 2015; 66: 343 359 [CrossRef] [PubMed]
    [Google Scholar]
  2. Collins SM, Bercik P. Gut microbiota: intestinal bacteria influence brain activity in healthy humans. Nat Rev Gastroenterol Hepatol 2013; 10: 326 327 [CrossRef] [PubMed]
    [Google Scholar]
  3. Dinan TG, Cryan JF. Gut-brain axis in 2016: Brain-gut-microbiota axis - mood, metabolism and behaviour. Nat Rev Gastroenterol Hepatol 2017; 14: 69 70 [CrossRef] [PubMed]
    [Google Scholar]
  4. Sharon G, Cruz NJ, Kang D-W, Gandal MJ, Wang B et al. Human gut microbiota from autism spectrum disorder promote behavioral symptoms in mice. Cell 2019; 177: 1600 1618 [CrossRef] [PubMed]
    [Google Scholar]
  5. Borre YE, Moloney RD, Clarke G, Dinan TG, Cryan JF. The impact of microbiota on brain and behavior: mechanisms & therapeutic potential. In Lyte M, Cryan J. (editors) Microbial endocrinology: The Microbiota-Gut-Brain Axis in Health and Disease. Advances in Experimental Medicine and Biology 817 New York: Springer; 2014 pp 373 403
    [Google Scholar]
  6. Matelski L, Van de Water J. Risk factors in autism: thinking outside the brain. J Autoimmun 2016; 67: 1 7 [CrossRef]
    [Google Scholar]
  7. MacFabe DF. Enteric short-chain fatty acids: microbial messengers of metabolism, mitochondria, and mind: implications in autism spectrum disorders. Microb Ecol Health Dis 2015; 26: 1 14 [CrossRef] [PubMed]
    [Google Scholar]
  8. MacFabe DF, Cain NE, Boon F, Ossenkopp K-P, 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: 47 54 [CrossRef] [PubMed]
    [Google Scholar]
  9. Dalile B, Van Oudenhove L, Vervliet B, Verbeke K. The role of short-chain fatty acids in microbiota-gut-brain communication. Nat Rev Gastroenterol Hepatol 2019; 16: 461 478 [CrossRef] [PubMed]
    [Google Scholar]
  10. Karaivazoglou K, Konstantakis C, Assimakopoulos SF, Triantos C. Neonate gut colonization: the rise of a social brain. Neurogastroenterol Motil 2019 e13767 [CrossRef] [PubMed]
    [Google Scholar]
  11. Braniste V, Al-Asmakh M, Kowal C, Anuar F, Abbaspour A et al. The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med 2014; 6: 263ra158 [CrossRef] [PubMed]
    [Google Scholar]
  12. Sajdel-Sulkowska EM, Makowska-Zubrycka M, Czarzasta K, Kasarello K, Aggarwal V et al. Common genetic variants link the abnormalities in the gut-brain axis in prematurity and autism. Cerebellum 2019; 18: 255 265 [CrossRef] [PubMed]
    [Google Scholar]
  13. Rojo D, Méndez-García C, Raczkowska BA, Bargiela R, Moya A et al. Exploring the human microbiome from multiple perspectives: factors altering its composition and function. FEMS Microbiol Rev 2017; 41: 453 478 [CrossRef] [PubMed]
    [Google Scholar]
  14. Vernocchi P, Del Chierico F, Putignani L. Gut microbiota profiling: metabolomics based approach to unravel compounds affecting human health. Front Microbiol 2016; 7: 1144 [CrossRef] [PubMed]
    [Google Scholar]
  15. Gillberg C, Coleman M. The Biology of the Autistic Syndromes , 3rd ed. London: Cambridge University Press; 2000 pp 197 205
    [Google Scholar]
  16. Wang L, Christophersen CT, Sorich MJ, Gerber JP, Angley MT et al. Elevated fecal short chain fatty acid and ammonia concentrations in children with autism spectrum disorder. Dig Dis Sci 2012; 57: 2096 2102 [CrossRef]
    [Google Scholar]
  17. Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 2013; 155: 1451 1463 [CrossRef] [PubMed]
    [Google Scholar]
  18. De Angelis M, Piccolo M, Vannini L, Siragusa S, De Giacomo A et al. Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS One 2013; 8: e76993 [CrossRef] [PubMed]
    [Google Scholar]
  19. Sandler RH, Finegold SM, Bolte ER, Buchanan CP, Maxwell AP et al. Short-Term benefit from oral vancomycin treatment of regressive-onset autism. J Child Neurol 2000; 15: 429 435 [CrossRef] [PubMed]
    [Google Scholar]
  20. Kumar H, Sharma B. Minocycline ameliorates prenatal valproic acid induced autistic behaviour, biochemistry and blood brain barrier impairments in rats. Brain Res 2016; 1630: 83 97 [CrossRef] [PubMed]
    [Google Scholar]
  21. Gondalia SV, Palombo EA, Knowles SR, Cox SB, Meyer D et al. Molecular characterisation of gastrointestinal microbiota of children with autism (with and without gastrointestinal dysfunction) and their neurotypical siblings. Autism Res 2012; 5: 419 427 [CrossRef] [PubMed]
    [Google Scholar]
  22. Son JS, Zheng LJ, Rowehl LM, Tian X, Zhang Y et al. Comparison of fecal microbiota in children with autism spectrum disorders and neurotypical siblings in the simons simplex collection. PLoS One 2015; 10: e137725 [CrossRef] [PubMed]
    [Google Scholar]
  23. Kovtun AS, Averina OV, Zakharevich NV, Kasianov AS, Danilenko VN. In silico identification of metagenomic signature describing neurometabolic potential of normal human gut microbiota. Russ J Genet 2018; 54: 1101 1110 [CrossRef]
    [Google Scholar]
  24. Milani C, Duranti S, Bottacini F, Casey E, Turroni F et al. The first microbial colonizers of the human gut: composition, activities, and health implications of the infant gut microbiota. Microbiol Mol Biol Rev 2017; 81: e00036 17 [CrossRef] [PubMed]
    [Google Scholar]
  25. Andrews S. FastQC: a quality control tool for high throughput sequence data. 2010 Available at http://www.bioinformatics.babraham.ac.uk/projects/fastqc .
  26. Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 2014; 30: 2114 2120 [CrossRef] [PubMed]
    [Google Scholar]
  27. Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nat Methods 2012; 9: 357 359 [CrossRef] [PubMed]
    [Google Scholar]
  28. Nurk S, Meleshko D, Korobeynikov A, Pevzner PA. metaSPAdes: a new versatile metagenomic assembler. Genome Res 2017; 27: 824 834 [CrossRef] [PubMed]
    [Google Scholar]
  29. Truong DT, Franzosa EA, Tickle TL, Scholz M, Weingart G et al. MetaPhlAn2 for enhanced metagenomic taxonomic profiling. Nat Methods 2015; 12: 902 903 [CrossRef] [PubMed]
    [Google Scholar]
  30. Zhu W, Lomsadze A, Borodovsky M. Ab initio gene identification in metagenomic sequences. Nucleic Acids Res 2010; 38: e132 [CrossRef] [PubMed]
    [Google Scholar]
  31. Wood DE, Salzberg SL. Kraken: ultrafast metagenomic sequence classification using exact alignments. Genome Biol 2014; 15: R46 [CrossRef] [PubMed]
    [Google Scholar]
  32. Kanehisa M, Sato Y, Kawashima M, Furumichi M, Tanabe M. Kegg as a reference resource for gene and protein annotation. Nucleic Acids Res 2016; 44: D457 D462 [CrossRef] [PubMed]
    [Google Scholar]
  33. Hughes HK, Rose D, Ashwood P. The gut microbiota and dysbiosis in autism spectrum disorders. Curr Neurol Neurosci Rep 2018; 18: 81 [CrossRef] [PubMed]
    [Google Scholar]
  34. Cheng S, Han B, Ding M, Wen Y, Ma M et al. Identifying psychiatric disorder-associated gut microbiota using microbiota-related gene set enrichment analysis. Brief Bioinform 2019 pii:bbz034 [CrossRef] [PubMed]
    [Google Scholar]
  35. De Angelis M, Francavilla R, Piccolo M, De Giacomo A, Gobbetti M. Autism spectrum disorders and intestinal microbiota. Gut Microbes 2015; 6: 207 213 [CrossRef] [PubMed]
    [Google Scholar]
  36. Tomova A, Husarova V, Lakatosova S, Bakos J, Vlkova B et al. Gastrointestinal microbiota in children with autism in Slovakia. Physiol Behav 2015; 138: 179 187 [CrossRef] [PubMed]
    [Google Scholar]
  37. Strati F, Cavalieri D, Albanese D, De Felice C, Donati C et al. New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome 2017; 5: 1 11 [CrossRef]
    [Google Scholar]
  38. Liu S, Li E, Sun Z, Fu D, Duan G et al. Altered gut microbiota and short chain fatty acids in Chinese children with autism spectrum disorder. Sci Rep 2019; 9: 287 [CrossRef] [PubMed]
    [Google Scholar]
  39. Sarkar A, Lehto SM, Harty S, Dinan TG, Cryan JF et al. Psychobiotics and the manipulation of bacteria-gut-brain signals. Trends Neurosci 2016; 39: 763 781 [CrossRef] [PubMed]
    [Google Scholar]
  40. Kang D-W, Ilhan ZE, Isern NG, Hoyt DW, Howsmon DP et al. Differences in fecal microbial metabolites and microbiota of children with autism spectrum disorders. Anaerobe 2018; 49: 121 131 [CrossRef] [PubMed]
    [Google Scholar]
  41. Dinan TG, Stanton C, Cryan JF. Psychobiotics: a novel class of psychotropic. Biol Psychiatry 2013; 74: 720 726 [CrossRef] [PubMed]
    [Google Scholar]
  42. Finegold SM. Therapy and epidemiology of autism-clostridial spores as key elements. Med Hypotheses 2008; 70: 508 511 [CrossRef] [PubMed]
    [Google Scholar]
  43. Larroya-García A, Navas-Carrillo D, Orenes-Piñero E. Impact of gut microbiota on neurological diseases: diet composition and novel treatments. Crit Rev Food Sci Nutr 2019; 59: 3102 3116 [CrossRef] [PubMed]
    [Google Scholar]
  44. Finegold SM, Dowd SE, Gontcharova V, Liu C, Henley KE et al. Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe 2010; 16: 444 453 [CrossRef] [PubMed]
    [Google Scholar]
  45. Ma B, Liang J, Dai M, Wang J, Luo J et al. Altered gut microbiota in Chinese children with autism spectrum disorders. Front Cell Infect Microbiol 2019; 9: 40 [CrossRef] [PubMed]
    [Google Scholar]
  46. MacFabe DF, Cain DP, Rodriguez-Capote K, Franklin AE, Hoffman JE et al. Neurobiological effects of intraventricular propionic acid in rats: possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders. Behav Brain Res 2007; 176: 149 169 [CrossRef] [PubMed]
    [Google Scholar]
  47. Saito Y, Sato T, Nomoto K, Tsuji H. Identification of phenol- and p-cresol-producing intestinal bacteria by using media supplemented with tyrosine and its metabolites. FEMS Microbiol Ecol 2018; 94: 1 11 [CrossRef] [PubMed]
    [Google Scholar]
  48. Hofer U. Microbiome: B. fragilis and the brain. Nat Rev Microbiol 2014; 12: 76 77 [CrossRef] [PubMed]
    [Google Scholar]
  49. Valles-Colomer M, Falony G, Darzi Y, Tigchelaar EF, Wang J et al. The neuroactive potential of the human gut microbiota in quality of life and depression. Nat Microbiol 2019; 4: 623 632 [CrossRef] [PubMed]
    [Google Scholar]
  50. Yunes RA, Poluektova EU, Dyachkova MS, Klimina KM, Kovtun AS et al. GABA production and structure of gadB/gadC genes in Lactobacillus and Bifidobacterium strains from human microbiota. Anaerobe 2016; 42: 197 204 [CrossRef] [PubMed]
    [Google Scholar]
  51. Averina OV, Danilenko VN. The human GM: role in the formation and functioning of nervous system. Microbiology 2017; 86: 1 19
    [Google Scholar]
  52. Klimina KM, Kasianov AS, Poluektova EU, Emelyanov KV, Voroshilova VN et al. Employing toxin-antitoxin genome markers for identification of Bifidobacterium and Lactobacillus strains in human metagenomes. PeerJ 2019; 7: e6554 [CrossRef] [PubMed]
    [Google Scholar]
  53. Strandwitz P, Kim KH, Terekhova D, Liu JK, Sharma A et al. GABA-modulating bacteria of the human gut microbiota. Nat Microbiol 2019; 4: 396 403 [CrossRef] [PubMed]
    [Google Scholar]
  54. Kovtun AS, Averina OV, Alekseeva MG, Danilenko VN. Antibiotic resistance genes in the gut microbiota of children with autistic spectrum disorder as possible predictors of the disease. Microb Drug Resist 2020 09 Jan 2020 [CrossRef] [PubMed]
    [Google Scholar]
  55. Buffington SA, Di Prisco GV, Auchtung TA, Ajami NJ, Petrosino JF et al. Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring. Cell 2016; 165: 1762 1775 [CrossRef] [PubMed]
    [Google Scholar]
  56. Fond G, Boukouaci W, Chevalier G, Regnault A, Eberl G et al. The "psychomicrobiotic": Targeting microbiota in major psychiatric disorders: A systematic review. Pathol Biol 2015; 63: 35 42 [CrossRef] [PubMed]
    [Google Scholar]
  57. Husain F, Tang K, Veeranagouda Y, Boente R, Patrick S et al. Novel large-scale chromosomal transfer in Bacteroides fragilis contributes to its pan-genome and rapid environmental adaptation. Microb Genom 2017; 3: e000136 [CrossRef] [PubMed]
    [Google Scholar]
  58. Martineau J, Barthélémy C, Jouve J, Muh JP, Lelord G. Monoamines (serotonin and catecholamines) and their derivatives in infantile autism: age-related changes and drug effects. Dev Med Child Neurol 1992; 34: 593 603 [CrossRef] [PubMed]
    [Google Scholar]
  59. Mulder EJ, Anderson GM, Kema IP, de Bildt A, van Lang NDJ et al. Platelet serotonin levels in pervasive developmental disorders and mental retardation: diagnostic group differences, within-group distribution, and behavioral correlates. J Am Acad Child Adolesc Psychiatry 2004; 43: 491 499 [CrossRef] [PubMed]
    [Google Scholar]
  60. Hendren RL, Bertoglio K, Ashwood P, Sharp F. Mechanistic biomarkers for autism treatment. Med Hypotheses 2009; 73: 950 954 [CrossRef] [PubMed]
    [Google Scholar]
  61. Alabdali A, Al-Ayadhi L, El-Ansary A. Association of social and cognitive impairment and biomarkers in autism spectrum disorders. J Neuroinflammation 2014; 11: 4 [CrossRef] [PubMed]
    [Google Scholar]
  62. Doyen C, Mighiu D, Kaye K, Colineaux C, Beaumanoir C et al. Melatonin in children with autistic spectrum disorders: recent and practical data. Eur Child Adolesc Psychiatry 2011; 20: 231 239 [CrossRef] [PubMed]
    [Google Scholar]
  63. Aldred S, Moore KM, Fitzgerald M, Waring RH. Plasma amino acid levels in children with autism and their families. J Autism Dev Disord 2003; 33: 93 97 [CrossRef] [PubMed]
    [Google Scholar]
  64. Noto A, Fanos V, Barberini L, Grapov D, Fattuoni C et al. The urinary metabolomics profile of an Italian autistic children population and their unaffected siblings. J Matern Fetal Neonatal Med 2014; 27: 46 52 [CrossRef] [PubMed]
    [Google Scholar]
  65. Frustaci A, Neri M, Cesario A, Adams JB, Domenici E et al. Oxidative stress-related biomarkers in autism: systematic review and meta-analyses. Free Radic Biol Med 2012; 52: 2128 2141 [CrossRef] [PubMed]
    [Google Scholar]
  66. Filipek PA, Juranek J, Nguyen MT, Cummings C, Gargus JJ. Relative carnitine deficiency in autism. J Autism Dev Disord 2004; 34: 615 623 [CrossRef] [PubMed]
    [Google Scholar]
  67. Ming X, Stein TP, Barnes V, Rhodes N, Guo L. Metabolic perturbance in autism spectrum disorders: a metabolomics study. J Proteome Res 2012; 11: 5856 5862 [CrossRef] [PubMed]
    [Google Scholar]
  68. Persico AM, Napolioni V. Urinary p-cresol in autism spectrum disorder. Neurotoxicol Teratol 2013; 36: 82 90 [CrossRef] [PubMed]
    [Google Scholar]
  69. Mack DR. D(-)-lactic acid-producing probiotics, D(-)-lactic acidosis and infants. Can J Gastroenterol 2004; 18: 671 675 [CrossRef] [PubMed]
    [Google Scholar]
  70. Wang L, Christophersen CT, Sorich MJ, Gerber JP, Angley MT et al. Elevated fecal short chain fatty acid and ammonia concentrations in children with autism spectrum disorder. Dig Dis Sci 2012; 57: 2096 2102 [CrossRef] [PubMed]
    [Google Scholar]
  71. Zecavati N, Spence SJ. Neurometabolic disorders and dysfunction in autism spectrum disorders. Curr Neurol Neurosci Rep 2009; 9: 129 136 [CrossRef] [PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jmm/10.1099/jmm.0.001178
Loading
/content/journal/jmm/10.1099/jmm.0.001178
Loading

Data & Media loading...

Supplements

Supplementary material 2

PDF

Supplementary material 1

EXCEL
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error