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Gut microbiota and dietary patterns in children with attention-deficit/hyperactivity disorder

  • Liang-Jen Wang
  • Chia-Yu Yang
  • Wen-Jiun Chou
  • Min-Jing Lee
  • Miao-Chun Chou
  • Ho-Chang Kuo
  • Yuan-Ming Yeh
  • Sheng-Yu Lee
  • Lien-Hung Huang
  • Sung-Chou LiEmail author
Original Contribution

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, but the underlying pathophysiological mechanisms of ADHD remain unclear. Gut microbiota has been recognized to influence brain function and behaviors. Therefore, this study aimed to determine whether imbalanced gut microbiomes identified by a 16S rRNA sequencing approach are involved in the pathophysiology of ADHD. We recruited a total of 30 children with ADHD (mean age: 8.4 years) and a total of 30 healthy controls (mean age: 9.3 years) for this study. The dietary patterns of all participants were assessed with the food frequency questionnaire. The microbiota of fecal samples were investigated using 16S rRNA V3V4 amplicon sequencing, followed by bioinformatics and statistical analyses. We found that the gut microbiota communities in ADHD patients showed a significantly higher Shannon index and Chao index than the control subjects. Furthermore, the linear discriminant analysis effect size (LEfSe) analysis was used to identify differentially enriched bacteria between ADHD patients and healthy controls. The relative abundance of Bacteroides coprocola (B. coprocola) was decreased, while the relative abundance of Bacteroides uniformis (B. uniformis), Bacteroides ovatus (B. ovatus), and Sutterella stercoricanis (S. stercoricanis) were increased in the ADHD group. Of all participants, S. stercoricanis demonstrated a significant association with the intake of dairy, nuts/seeds/legumes, ferritin and magnesium. B. ovatus and S. stercoricanis were positively correlated to ADHD symptoms. In conclusion, we suggest that the gut microbiome community is associated with dietary patterns, and linked to the susceptibility to ADHD.

Keywords

ADHD Gut–brain axis 16S rRNA sequencing Microbiome Biomarker 

Notes

Acknowledgements

The authors would like to thank Professor Wei-Tsun Soong for granting us the use of the Chinese version of the K-SADS, and Professor Shur-Fen Gau for granting our use of the Chinese version of the SNAP-IV.

Funding

This work was supported by grant from the Chang Gung Memorial Hospital Research Grant (CMRPG8E1441) and the Taiwan Ministry of Science and Technology (MOST 107-2628-B-182-001).

Compliance with ethical standards

Conflict of interest

All authors declare no biomedical financial interests or potential conflicts of interest.

Supplementary material

787_2019_1352_MOESM1_ESM.jpg (225 kb)
Supplementary material 1 The distribution of enriched bacteria identified at genus level in the ADHD patients and healthy controls using LEfSe analysis. Linear discriminant analysis (LDA) plots at genus levels showed the enriched bacteria in ADHD patients and healthy controls (JPEG 225 kb)
787_2019_1352_MOESM2_ESM.docx (24 kb)
Supplementary material 2 (DOCX 23 kb)

References

  1. 1.
    Polanczyk GV, Willcutt EG, Salum GA, Kieling C, Rohde LA (2014) ADHD prevalence estimates across three decades: an updated systematic review and meta-regression analysis. Int J Epidemiol 43(2):434–442CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders (DSM-IV-TR). American Psychiatric Association, WashingtonGoogle Scholar
  3. 3.
    Spencer TJ, Biederman J, Mick E (2007) Attention-deficit/hyperactivity disorder: diagnosis, lifespan, comorbidities, and neurobiology. J Pediatr Psychol 32(6):631–642CrossRefGoogle Scholar
  4. 4.
    Stilling RM, Dinan TG, Cryan JF (2014) Microbial genes, brain and behaviour—epigenetic regulation of the gut–brain axis. Genes Brain Behav 13(1):69–86CrossRefGoogle Scholar
  5. 5.
    Montiel-Castro AJ, Gonzalez-Cervantes RM, Bravo-Ruiseco G, Pacheco-Lopez G (2013) The microbiota-gut–brain axis: neurobehavioral correlates, health and sociality. Front Integr Neurosci 7:70CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Lima-Ojeda JM, Rupprecht R, Baghai TC (2017) “I Am I and My Bacterial Circumstances”: linking gut microbiome, neurodevelopment, and depression. Front Psychiatry 8:153CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Sandgren AM, Brummer RJM (2018) ADHD-originating in the gut? The emergence of a new explanatory model. Med Hypotheses 120:135–145CrossRefPubMedGoogle Scholar
  8. 8.
    Yadav M, Verma MK, Chauhan NS (2018) A review of metabolic potential of human gut microbiome in human nutrition. Arch Microbiol 200(2):203–217CrossRefPubMedGoogle Scholar
  9. 9.
    Borre YE, O’Keeffe GW, Clarke G, Stanton C, Dinan TG, Cryan JF (2014) Microbiota and neurodevelopmental windows: implications for brain disorders. Trends Mol Med 20(9):509–518CrossRefPubMedGoogle Scholar
  10. 10.
    Cenit MC, Nuevo IC, Codoner-Franch P, Dinan TG, Sanz Y (2017) Gut microbiota and attention deficit hyperactivity disorder: new perspectives for a challenging condition. Eur Child Adolesc Psychiatry 26(9):1081–1092CrossRefPubMedGoogle Scholar
  11. 11.
    Dore J, Blottiere H (2015) The influence of diet on the gut microbiota and its consequences for health. Curr Opin Biotechnol 32:195–199CrossRefPubMedGoogle Scholar
  12. 12.
    Principi N, Esposito S (2016) Gut microbiota and central nervous system development. J Infect 73(6):536–546CrossRefPubMedGoogle Scholar
  13. 13.
    Felice VD, O’Mahony SM (2017) The microbiome and disorders of the central nervous system. Pharmacol Biochem Behav 160:1–13CrossRefPubMedGoogle Scholar
  14. 14.
    Slykerman RF, Thompson J, Waldie KE, Murphy R, Wall C, Mitchell EA (2017) Antibiotics in the first year of life and subsequent neurocognitive outcomes. Acta Paediatr 106(1):87–94CrossRefPubMedGoogle Scholar
  15. 15.
    Partty A, Kalliomaki M, Wacklin P, Salminen S, Isolauri E (2015) A possible link between early probiotic intervention and the risk of neuropsychiatric disorders later in childhood: a randomized trial. Pediatr Res 77(6):823–828CrossRefPubMedGoogle Scholar
  16. 16.
    Park S, Cho SC, Hong YC, Oh SY, Kim JW, Shin MS, Kim BN, Yoo HJ, Cho IH, Bhang SY (2012) Association between dietary behaviors and attention-deficit/hyperactivity disorder and learning disabilities in school-aged children. Psychiatry Res 198(3):468–476CrossRefPubMedGoogle Scholar
  17. 17.
    Stevenson J (2006) Dietary influences on cognitive development and behaviour in children. Proc Nutr Soc 65(4):361–365CrossRefPubMedGoogle Scholar
  18. 18.
    Sinn N (2008) Nutritional and dietary influences on attention deficit hyperactivity disorder. Nutr Rev 66(10):558–568CrossRefGoogle Scholar
  19. 19.
    Millichap JG, Yee MM (2012) The diet factor in attention-deficit/hyperactivity disorder. Pediatrics 129(2):330–337CrossRefGoogle Scholar
  20. 20.
    Bibbo S, Ianiro G, Giorgio V, Scaldaferri F, Masucci L, Gasbarrini A, Cammarota G (2016) The role of diet on gut microbiota composition. Eur Rev Med Pharmacol Sci 20(22):4742–4749PubMedGoogle Scholar
  21. 21.
    Wang WL, Xu SY, Ren ZG, Tao L, Jiang JW, Zheng SS (2015) Application of metagenomics in the human gut microbiome. World J Gastroenterol 21(3):803–814CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Bragg L, Tyson GW (2014) Metagenomics using next-generation sequencing. Methods Mol Biol 1096:183–201CrossRefPubMedGoogle Scholar
  23. 23.
    Janda JM, Abbott SL (2007) 16S rRNA gene sequencing for bacterial identification in the diagnostic laboratory: pluses, perils, and pitfalls. J Clin Microbiol 45(9):2761–2764CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Caporaso JG, Lauber CL, Walters WA, Berg-Lyons D, Lozupone CA, Turnbaugh PJ, Fierer N, Knight R (2011) Global patterns of 16S rRNA diversity at a depth of millions of sequences per sample. Proc Natl Acad Sci USA 108(Suppl 1):4516–4522CrossRefPubMedGoogle Scholar
  25. 25.
    Culligan EP, Marchesi JR, Hill C, Sleator RD (2014) Combined metagenomic and phenomic approaches identify a novel salt tolerance gene from the human gut microbiome. Front Microbiol 5:189CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Gilbert JA, Dupont CL (2011) Microbial metagenomics: beyond the genome. Ann Rev Mar Sci 3:347–371CrossRefPubMedGoogle Scholar
  27. 27.
    Oulas A, Pavloudi C, Polymenakou P, Pavlopoulos GA, Papanikolaou N, Kotoulas G, Arvanitidis C, Iliopoulos I (2015) Metagenomics: tools and insights for analyzing next-generation sequencing data derived from biodiversity studies. Bioinform Biol Insights 9:75–88CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Aarts E, Ederveen THA, Naaijen J, Zwiers MP, Boekhorst J, Timmerman HM, Smeekens SP, Netea MG, Buitelaar JK, Franke B, van Hijum S, Arias Vasquez A (2017) Gut microbiome in ADHD and its relation to neural reward anticipation. PLoS One 12(9):e0183509CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Jiang HY, Zhou YY, Zhou GL, Li YC, Yuan J, Li XH, Ruan B (2018) Gut microbiota profiles in treatment-naive children with attention deficit hyperactivity disorder. Behav Brain Res 347:408–413CrossRefPubMedGoogle Scholar
  30. 30.
    Prehn-Kristensen A, Zimmermann A, Tittmann L, Lieb W, Schreiber S, Baving L, Fischer A (2018) Reduced microbiome alpha diversity in young patients with ADHD. PLoS One 13(7):e0200728CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P, Williamson D, Ryan N (1997) Schedule for affective disorders and schizophrenia for school-age children-present and lifetime version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry 36(7):980–988CrossRefGoogle Scholar
  32. 32.
    Gau SF, Soong WT (1999) Psychiatric comorbidity of adolescents with sleep terrors or sleepwalking: a case-control study. Aust N Z J Psychiatry 33(5):734–739CrossRefPubMedGoogle Scholar
  33. 33.
    Baron IS (2005) Test review: wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV). Child Neuropsychol 11(5):471–475CrossRefPubMedGoogle Scholar
  34. 34.
    Bussing R, Fernandez M, Harwood M, Wei H, Garvan CW, Eyberg SM, Swanson JM (2008) Parent and teacher SNAP-IV ratings of attention deficit hyperactivity disorder symptoms: psychometric properties and normative ratings from a school district sample. Assessment 15(3):317–328CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Gau SS, Lin CH, Hu FC, Shang CY, Swanson JM, Liu YC, Liu SK (2009) Psychometric properties of the Chinese version of the Swanson, Nolan, and Pelham, Version IV Scale-Teacher Form. J Pediatr Psychol 34(8):850–861CrossRefPubMedGoogle Scholar
  36. 36.
    Gau SS, Shang CY, Liu SK, Lin CH, Swanson JM, Liu YC, Tu CL (2008) Psychometric properties of the Chinese version of the Swanson, Nolan, and Pelham, version IV scale—parent form. Int J Methods Psychiatr Res 17(1):35–44CrossRefGoogle Scholar
  37. 37.
    Zhang S, Faries DE, Vowles M, Michelson D (2005) ADHD Rating scale IV: psychometric properties from a multinational study as a clinician-administered instrument. Int J Methods Psychiatr Res 14(4):186–201CrossRefPubMedGoogle Scholar
  38. 38.
    Lee MS, Pan WH, Liu KL, Yu MS (2006) Reproducibility and validity of a Chinese food frequency questionnaire used in Taiwan. Asia Pac J Clin Nutr 15(2):161–169PubMedGoogle Scholar
  39. 39.
    Chou WJ, Lee MF, Hou ML, Hsiao LS, Lee MJ, Chou MC, Wang LJ (2018) Dietary and nutrient status of children with attention-deficit/hyperactivity disorder: a case-control study. Asia Pac J Clin Nutr 27(6):1325–1331PubMedGoogle Scholar
  40. 40.
    Schloss PD, Westcott SL, Ryabin T, Hall JR, Hartmann M, Hollister EB, Lesniewski RA, Oakley BB, Parks DH, Robinson CJ, Sahl JW, Stres B, Thallinger GG, Van Horn DJ, Weber CF (2009) Introducing mothur: open-source, platform-independent, community-supported software for describing and comparing microbial communities. Appl Environ Microbiol 75(23):7537–7541CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Kozich JJ, Westcott SL, Baxter NT, Highlander SK, Schloss PD (2013) Development of a dual-index sequencing strategy and curation pipeline for analyzing amplicon sequence data on the MiSeq Illumina sequencing platform. Appl Environ Microbiol 79(17):5112–5120CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Edgar RC, Haas BJ, Clemente JC, Quince C, Knight R (2011) UCHIME improves sensitivity and speed of chimera detection. Bioinformatics 27(16):2194–2200CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Wang Q, Garrity GM, Tiedje JM, Cole JR (2007) Naive Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy. Appl Environ Microbiol 73(16):5261–5267CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Caporaso JG, Kuczynski J, Stombaugh J, Bittinger K, Bushman FD, Costello EK, Fierer N, Pena AG, Goodrich JK, Gordon JI, Huttley GA, Kelley ST, Knights D, Koenig JE, Ley RE, Lozupone CA, McDonald D, Muegge BD, Pirrung M, Reeder J, Sevinsky JR, Turnbaugh PJ, Walters WA, Widmann J, Yatsunenko T, Zaneveld J, Knight R (2010) QIIME allows analysis of high-throughput community sequencing data. Nat Methods 7(5):335–336CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Segata N, Izard J, Waldron L, Gevers D, Miropolsky L, Garrett WS, Huttenhower C (2011) Metagenomic biomarker discovery and explanation. Genome Biol 12(6):R60CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Morgan XC, Huttenhower C (2012) Chapter 12: human microbiome analysis. PLoS Comput Biol 8(12):e1002808CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Bercik P, Denou E, Collins J, Jackson W, Lu J, Jury J, Deng Y, Blennerhassett P, Macri J, McCoy KD, Verdu EF, Collins SM (2011) The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 141(2):599–609 (609, e591–593) CrossRefGoogle Scholar
  48. 48.
    Clarke G, Grenham S, Scully P, Fitzgerald P, Moloney RD, Shanahan F, Dinan TG, Cryan JF (2013) The microbiome-gut–brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry 18(6):666–673CrossRefGoogle Scholar
  49. 49.
    Sherman MP, Zaghouani H, Niklas V (2015) Gut microbiota, the immune system, and diet influence the neonatal gut–brain axis. Pediatr Res 77(1–2):127–135CrossRefPubMedGoogle Scholar
  50. 50.
    Wang Y, Kasper LH (2014) The role of microbiome in central nervous system disorders. Brain Behav Immun 38:1–12CrossRefGoogle Scholar
  51. 51.
    Mayer EA, Tillisch K, Gupta A (2015) Gut–brain axis and the microbiota. J Clin Invest 125(3):926–938CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Wexler HM (2007) Bacteroides: the good, the bad, and the nitty-gritty. Clin Microbiol Rev 20(4):593–621CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Renouf M, Hendrich S (2011) Bacteroides uniformis is a putative bacterial species associated with the degradation of the isoflavone genistein in human feces. J Nutr 141(6):1120–1126CrossRefPubMedGoogle Scholar
  54. 54.
    NCBI: Bacteroides ovatus. In: Normal gut bacterium. 2019. https://www.ncbi.nlm.nih.gov/genome/?term=Bacteroides%20ovatus
  55. 55.
    Wu M, McNulty NP, Rodionov DA, Khoroshkin MS, Griffin NW, Cheng J, Latreille P, Kerstetter RA, Terrapon N, Henrissat B, Osterman AL, Gordon JI (2015) Genetic determinants of in vivo fitness and diet responsiveness in multiple human gut Bacteroides. Science 350(6256):aac5992CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Coyne MJ, Roelofs KG, Comstock LE (2016) Type VI secretion systems of human gut Bacteroidales segregate into three genetic architectures, two of which are contained on mobile genetic elements. BMC Genomics 17:58CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Kitahara M, Sakamoto M, Ike M, Sakata S, Benno Y (2005) Bacteroides plebeius sp. nov. and Bacteroides coprocola sp. nov., isolated from human faeces. Int J Syst Evol Microbiol 55(Pt 5):2143–2147CrossRefPubMedGoogle Scholar
  58. 58.
    Tillisch K, Mayer EA, Gupta A, Gill Z, Brazeilles R, Le Neve B, van Hylckama Vlieg JET, Guyonnet D, Derrien M, Labus JS (2017) Brain structure and response to emotional stimuli as related to gut microbial profiles in healthy women. Psychosom Med 79(8):905–913CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Greetham HL, Collins MD, Gibson GR, Giffard C, Falsen E, Lawson PA (2004) Sutterella stercoricanis sp. nov., isolated from canine faeces. Int J Syst Evol Microbiol 54(Pt 5):1581–1584CrossRefPubMedGoogle Scholar
  60. 60.
    Williams BL, Hornig M, Parekh T, Lipkin WI (2012) 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 3(1):e00261CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Wang LJ, Yu YH, Fu ML, Yeh WT, Hsu JL, Yang YH, Chen WJ, Chiang BL, Pan WH (2018) Attention deficit-hyperactivity disorder is associated with allergic symptoms and low levels of hemoglobin and serotonin. Sci Rep 8(1):10229CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Chou WJ, Lee MF, Hou ML, Hsiao LS, Lee MJ, Chou MC, Wang LJ (2018) Dietary and nutrient status of children with attention-deficit/hyperactivity disorder: a case-control study. Asia Pac J Clin Nutr 27(6):1325–1331PubMedGoogle Scholar
  63. 63.
    Proctor C, Thiennimitr P, Chattipakorn N, Chattipakorn SC (2017) Diet, gut microbiota and cognition. Metab Brain Dis 32(1):1–17CrossRefPubMedGoogle Scholar
  64. 64.
    Diaz Heijtz R, Wang S, Anuar F, Qian Y, Bjorkholm B, Samuelsson A, Hibberd ML, Forssberg H, Pettersson S (2011) Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci USA 108(7):3047–3052CrossRefPubMedGoogle Scholar
  65. 65.
    Hopkins MJ, Sharp R, Macfarlane GT (2002) Variation in human intestinal microbiota with age. Dig Liver Dis 34(Suppl 2):S12–S18CrossRefPubMedGoogle Scholar
  66. 66.
    Axelsson PB, Clausen TD, Petersen AH, Hageman I, Pinborg A, Kessing LV, Bergholt T, Rasmussen SC, Keiding N, Lokkegaard ECL (2019) Investigating the effects of cesarean delivery and antibiotic use in early childhood on risk of later attention deficit hyperactivity disorder. J Child Psychol Psychiatry 60(2):151–159CrossRefPubMedGoogle Scholar
  67. 67.
    Liu YCLS, Shang CY, Lin CH, Tu CL, Gau SF (2006) Norm of the Chinese version of the Swanson, Nolan and Pelham, version IV scale for ADHD. Taiwan J Psychiatry 20:290–304Google Scholar
  68. 68.
    Jain A, Li XH, Chen WN (2018) Similarities and differences in gut microbiome composition correlate with dietary patterns of Indian and Chinese adults. AMB Express 8(1):104CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Liang-Jen Wang
    • 1
    • 2
  • Chia-Yu Yang
    • 3
    • 4
  • Wen-Jiun Chou
    • 1
  • Min-Jing Lee
    • 1
  • Miao-Chun Chou
    • 1
  • Ho-Chang Kuo
    • 5
    • 6
  • Yuan-Ming Yeh
    • 7
    • 8
  • Sheng-Yu Lee
    • 9
    • 10
  • Lien-Hung Huang
    • 11
  • Sung-Chou Li
    • 11
    Email author
  1. 1.Department of Child and Adolescent PsychiatryKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiungTaiwan
  2. 2.Department of Chinese MedicineChang Gung UniversityTaoyuanTaiwan
  3. 3.Department of Microbiology and Immunology/Molecular Medicine Research CenterChang Gung UniversityTaoyuanTaiwan
  4. 4.Division of Colon and Rectal SurgeryChang Gung Memorial HospitalLinkouTaiwan
  5. 5.Department of PediatricsKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiungTaiwan
  6. 6.Kawasaki Disease CenterKaohsiung Chang Gung Memorial HospitalKaohsiungTaiwan
  7. 7.Molecular Medicine Research CenterChang Gung UniversityTaoyuanTaiwan
  8. 8.Genomic Medicine Research Core LaboratoryChang Gung Memorial HospitalLinkouTaiwan
  9. 9.Department of PsychiatryKaohsiung Veterans General HospitalKaohsiungTaiwan
  10. 10.Department of Psychiatry, College of MedicineNational Yang-Ming UniversityTaipeiTaiwan
  11. 11.Genomics and Proteomics Core Laboratory, Department of Medical ResearchKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung CityTaiwan

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