Abstract
Attention-deficit hyperactivity disorder (ADHD) etiology is not completely understood, but common comorbid dysfunction of the gastrointestinal and immune system suggests that these systems may be affected by a common genetic background and molecular mechanisms. For example, increased levels of specific cytokines were observed in ADHD. Moreover, ADHD has a high comorbidity with both Th1- and Th2-mediated disorders like ear infections, eczema and asthma. A common pathophysiological mechanism was suggested to underlie both asthma and ADHD, while several genes that are linked to ADHD have immune functions. Furthermore, immunological recognition of food provoking ADHD-like behavior was suggested. An immune imbalance, probably requiring a predisposing genetic background, is therefore suggested to contribute to ADHD etiology, with immune dysregulation being more likely than a single subcellular defect. However, next to allergic mechanisms, also pharmacological mechanisms (especially in case of food additives) might be involved. In addition, though cellular (cytokine-related) rather than antibody-mediated immune mechanisms seem involved, specific immune-inflammatory markers other than antibodies have not been systematically studied in ADHD. Substantial alterations implicated in ADHD apparently occur in the immune system and epigenetic regulation of gene expression. As a result, chronic inflammation and oxidative stress could develop, which can lead to ADHD symptoms, for example by chronic T-cell-mediated neuroinflammation. If immune pathways contribute to ADHD, both its diagnosis and treatment should be reconsidered. Modulation of immune system activity might have potential in ADHD treatment, for example by nutritional approaches providing safe and low-cost ADHD therapy, but further research in these fields is implicated.
This is a preview of subscription content, access via your institution.

References
- 1.
Bierderman J, Faraone SV (2005) Attention-deficit hyperactivity disorder. Lancet 366:237–248
- 2.
Stevens LJ, Kuczek T, Burgess JR, Hurt E, Arnold LE (2011) Dietary sensitivities and ADHD symptoms: 35 years of research. Clin Pediatr 50:279–293
- 3.
Danckaerts M, Sonuga-Barke EJS, Banaschewski T et al (2010) The quality of life of children with attention deficit/hyperactivity disorder: a systematic review. Eur Child Adolesc Psychiatr 19:83–105
- 4.
Pelham WE, Foster EM, Robb JA (2007) The economic impact of attention-deficit/hyperactivity disorder in children and adolescents. J Pediatr Psychol 32:711–727
- 5.
Arns M, van der Heijden KB, Arnold LE, Kenemans JL (2013) Geographic variation in the prevalence of attention-deficit/hyperactivity disorder: the sunny perspective. Biol Psychiatry 74:585–590
- 6.
Schachter HM, Pham B, King J, Langford S, Moher D (2011) How efficacious and safe is short-acting methylphenidate for the treatment of attention-deficit hyperactivity disorder in children and adolescents? A meta-analysis. CMAJ 165:1475–1488
- 7.
Shibib S, Chalhoub N (2009) Stimulant induced psychosis. Child Adolesc Ment Health 14:20–23
- 8.
Westover AN, Halm EA (2012) Do prescription stimulants increase the risk of adverse cardiovascular events? A systematic review. BMC Cardiovasc Disord 12:41–50
- 9.
Martinez-Raga J, Knecht C, Szerman N, Martinez MI (2013) Risk of serious cardiovascular problems with medications for attention-deficit hyperactivity disorder. CNS Drugs 27:15–30
- 10.
Silva RR, Skimming JW, Muniz R (2010) Cardiovascular safety of stimulant medications for pediatric attention-deficit hyperactivity disorder. Clin Pediatr (Phila) 49:840–851
- 11.
Antshel KM, Hargrave TM, Simonescu M, Kaul P, Hendricks K, Faraone SV (2011) Advances in understanding and treating ADHD. BMC Med 9:72
- 12.
Steer CR (2005) Managing attention deficit/hyperactivity disorder: unmet needs and future directions. Arch Dis Child 90:119–125
- 13.
Charach A, Fernandez R (2013) Enhancing ADHD medication adherence: challenges and opportunities. Curr Psychiatr Rep 15:371–379
- 14.
Wallis D, Russell HF, Muenke M (2008) Review: genetics of attention deficit/hyperactivity disorder. J Pediatr Psychol 33:1085–1099
- 15.
Poelmans G, Pauls DL, Buitelaar JK, Franke B (2011) Integrated Genome-Wide Association Study Findings: identification of a neurodevelopmental network for attention deficit hyperactivity disorder. Am J Psychiatr 168:365–377
- 16.
Corradini I, Verderio C, Sala M, Wilson MC, Matteoli M (2009) SNAP-25 in neuropsychiatric disorders. Ann NY Acad Sci 1152:93–99
- 17.
Faraone SV, Perlis RH, Doyle AE et al (2005) Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry 57:1313–1323
- 18.
Weber H, Scholz C-J, Jacob CP et al (2013) SPOCK3, a risk gene for adult ADHD and personality disorders. Eur Arch Psychiatry Clin Neurosci [Epub ahead of print]
- 19.
Albayrak Ö, Pütter C, Volckmar AL, Psychiatric GWAS Consortium: ADHD subgroup et al (2013) Common obesity risk alleles in childhood attention-deficit/hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet 162B:295–305
- 20.
Hinney A, Scherag A, Jarick I, Psychiatric GWAS Consortium: ADHD subgroup et al (2011) Genome-wide association study in German patients with attention deficit/hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet 156B:888–897
- 21.
Smoller JW, Ripke S, Lee PH, Cross-Disorder Group of the Psychiatric Genomics Consortium; Genetic Risk Outcome of Psychosis (GROUP) Consortium et al (2013) Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 381:1371–1379
- 22.
Lee SH, Ripke S, Neale BM, Cross-Disorder Group of the Psychiatric Genomics Consortium et al (2013) Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet 45:984–994
- 23.
Hochberg Z, Feil R, Constancia M et al (2011) Child health, developmental plasticity, and epigenetic programming. Endocr Rev 32:159–224
- 24.
Millichap JG (2008) Etiologic classification of attention-deficit/hyperactivity disorder. Pediatrics 121:e358–e365
- 25.
Feder A, Nestler EJ, Westphal M, Charney DS (2010) Psychobiological mechanisms of resilience to stress. In: Reich JW, Zautra AJ, Hall JS (eds) Handbook of adult resilience. The Guilford Press, New York, pp 35–54
- 26.
Martino M, Rocchi G, Escelsior A, Fornaro M (2012) Immunomodulation mechanism of antidepressants: interactions between serotonin/norepinephrine balance and Th1/Th2 balance. Curr Neuropharmacol 10:97–123
- 27.
Xiang L, Marshall GD Jr (2011) Immunomodulatory effect of in vitro stress hormones on Foxp3, Th1/Th2 cytokine and costimulatory molecule mRNA expression in human peripheral blood mononuclear cells. NeuroImmunoModulation 18:1–10
- 28.
Ma L, Chen YH, Chen H, Liu YY, Wang YX (2011) The function of hypothalamus-pituitary-adrenal axis in children with ADHD. Brain Res 1368:159–162
- 29.
Scahill L, deGraft-Johnson A (1997) Food allergies, asthma, and attention deficit hyperactivity disorder. JCAPN 10:36–40
- 30.
Pelsser LM, Buitelaar JK, Savelkoul HFJ (2009) ADHD as a (non) allergic hypersensitivity disorder: A hypothesis. Pediatr Allergy Immunol 20:107–112
- 31.
Sinn N (2008) Nutritional and dietary influences on attention deficit hyperactivity disorder. Nutr Rev 66:558–568
- 32.
Millichap JG, Yee MM (2012) The diet factor in attention-deficit/hyperactivity disorder. Pediatrics 129:330–337
- 33.
Pelsser LM, Frankena K, Toorman J et al (2011) Effects of a restricted elimination diet on the behavior of children with attention-deficit hyperactivity disorder (INCA study): a randomized controlled trial. Lancet 377:494–503
- 34.
Schonwald A (2008) ADHD and Food Additives Revisited. AAP Grand Rounds 19:17
- 35.
Schab DW, Trinh NT (2004) Do artificial food colors promote hyperactivity in children with hyperactive syndromes? A meta-analysis of double-blind placebo-controlled trials. J Dev Behav Pediatr 25:423–434
- 36.
Bateman B, Warner JO, Hutchinson E et al (2004) The effects of a double blind, placebo controlled, artificial food colourings and benzoate preservative challenge on hyperactivity in a general population sample of preschool children. Arch Dis Child 89:506–511
- 37.
Nigg JT, Lewis K, Edinger T, Falk M (2012) Meta-analysis of attention-deficit/hyperactivity disorder or attention-deficit/hyperactivity disorder symptoms, restriction diet, and synthetic food color additives. J Am Acad Child Adolesc Psychiatr 51:86–97
- 38.
National Collaborating Centre for Mental Health commissioned by the National Institute for Health and Clinical Excellence (NICE) (2009) Attention deficit hyperactivity disorder: Diagnosis and management of ADHD in children, young people and adults. National Clinical Practice Guideline Number 72. Leicester and London: The British Psychological Society and The Royal College of Psychiatrist
- 39.
Rowe KS, Rowe KJ (1994) Synthetic food coloring and behavior: a dose response effect in a double-blind, placebo-controlled, repeated-measures study. J Pediatr 125:694–698
- 40.
Gillies D, Sinn JKH, Lad SS, Leach MJ, Ross MJ (2012) Polyunsaturated fatty acids (PUFA) for attention deficit hyperactivity disorder (ADHD) in children and adolescents (review). Cochrane Database Syst Rev 7:CD007986
- 41.
Arnold LE, DiSilvestro RA (2005) Zinc in attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 15:619–627
- 42.
Konofal E, Lecendreux M, Arnulf I, Mouren MC (2004) Iron deficiency in children with attention-deficit/hyperactivity disorder. Arch Pediatr Adolesc Med 158:1113–1115
- 43.
Egger J, Graham PJ, Carter CM, Gumley D, Soothill JF (1985) Controlled trial of oligo-antigenic treatment in hyperkinetic syndrome. Lancet 325:540–545
- 44.
Carter CM, Ubanowicz M, Hemsley R et al (1993) Effects of a few food diet on attention deficit disorder. Arch Dis Child 69:564–568
- 45.
Stevens LJ, Kuczek T, Burgess JR, Stochelski MA, Arnold LE, Galland L (2013) Mechanisms of behavioral, atopic, and other reactions to artificial food colors in children. Nutr Rev 71:268–281
- 46.
Gaitens T, Kaplan BJ, Freigang B (1998) Absence of an association between IgE-mediated atopic responsiveness and ADHD symptomatology. J Child Psychol Psychiatr 39:427–431
- 47.
Egger J, Stolla A, McEwen LM (1992) Controlled trial of hyposensitisation in children with food-induced hyperkinetic syndrome. Lancet 339:1150–1153
- 48.
El-Ansary A, Shaker GH, Rizk MZ (2013) Role of gut–brain axis in the aetiology of neurodevelopmental disorders with reference to autism. J Clinic Toxicol S6
- 49.
Lupp C, Robertson ML, Wickham ME (2007) Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae. Cell Host Microbe 2:119–129
- 50.
Stevens LJ, Zentall SS, Deck JL et al (1995) Essential fatty acid metabolism in boys with attention-deficit hyperactivity disorder. Am J Clin Nutr 62:761–768
- 51.
Schmitt J, Romanos M, Schmitt NM, Meurer M, Kirch W (2009) Atopic eczema and attention-deficit/hyperactive disorder in a population based–based sample of children and adolescents. JAMA 301:724–726
- 52.
Fasmer OB, Halmoy A, Eagen TM, Oedegaard KJ, Haavik J (2011) Adult attention deficit hyperactivity disorder is associated with asthma. BMC Psychiatr 11:128–134
- 53.
Buske-Kirschbaum A, Schmitt J, Plessowa F, Romanos M, Weidinger S, Roessner V (2013) Psychoendocrine and psychoneuroimmunological mechanisms in the comorbidity of atopic eczema and attention deficit/hyperactivity disorder. Psychoneuroendocrinology 38:12–23
- 54.
Marshall P (1989) Attention deficit disorder and allergy: a neurochemical model of the relation between the illnesses. Psychol Bull 106:434–446
- 55.
Millichap JG (2011) Attention deficit hyperactivity disorder handbook. A physician’s guide to ADHD, 2nd edn. Springer Science + Business Media, New York
- 56.
Egger J, Stolla A, McEwen LM (1993) Hyposensitisation for food-induced hyperkinetic syndrome. Lancet 341:115
- 57.
Bengmark S (2013) Gut microbiota, immune development and function. Pharmacol Res 69:87–113
- 58.
Jyonouchi H (2008) Non-IgE mediated food allergy. Inflamm Allergy Drug Targets 7:173–180
- 59.
Nopoulos P, Berg S, Castellenos FX, Delgado A, Andreasen NC, Rapoport JL (2000) Developmental brain anomalies in children with attention-deficit hyperactivity disorder. J Child Neurol 15:102–108
- 60.
Russell VA (2011) Overview of animal models of attention deficit hyperactivity disorder (ADHD). Curr Protoc Neurosci 9(9):35
- 61.
Chen H, Centola M, Altschul SF, Metzger H (1998) Characterization of gene expression in resting and activated mast cells. J Exp Med 188:1657–1668
- 62.
Tsai SJ (2006) Signal transducer and activator of transcription 6 (STAT6) and attention-deficit hyperactivity disorder: a speculative hypothesis. Med Hypotheses 67:1341–1343
- 63.
Ogdie MN, Macphie L, Minassian SL et al (2003) A genome wide scan for attention-deficit/hyperactivity disorder in an extended sample: suggestive linkage on 17p11. Am J Hum Genet 72:1268–1279
- 64.
Aureli A, Sebastiani P, Del Beato T et al (2008) Investigation on the possible relationship existing between the HLA-DR gene and attention deficit hyperactivity disorder and/or mental retardation. Int J Immunopathol Pharma 21:985–991
- 65.
Pineda DA, Palacio LG, Puerta IC et al (2007) Environmental influences that affect attention deficit/hyperactivity disorder—Study of a genetic isolate. Eur Child Adolesc Psychiatr 16:337–346
- 66.
Roza SJ, Steegers EAP, Verburg BO et al (2008) What is spared by fetal brain-sparing? Fetal circulatory redistribution and behavioral problems in the general population. Am J Epidemiol 168:1145–1152
- 67.
Hüppi PS (2008) Neuroimaging of brain development—discovering the origins of neuropsychiatric disorders? Ped Res 64:325
- 68.
Murphy TK, Kurlan R, Leckman J (2010) The immunobiology of Tourette’s disorder, pediatric autoimmune neuropsychiatric disorders associated with streptococcus, and related disorders: a way forward. J Child Adolesc Psychopharmacol 20:317–331
- 69.
Smith SE, Li J, Garbett K, Mirnics K, Patterson PH (2007) Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci 27:10695–10702
- 70.
Meyer U, Feldon J, Yee BK (2009) A review of the fetal brain cytokine imbalance hypothesis of schizophrenia. Schizophr Bull 35:959–972
- 71.
Cochrane S, Beyer K, Clausen M et al (2009) Factors influencing the incidence and prevalence of food allergy. Allergy 64:1246–1255
- 72.
Shyu CS, Lin HK, Lin CH, Fu LS (2012) Prevalence of attention-deficit/hyperactivity disorder in patients with pediatric allergic disorders: a nationwide, population-based study. J Micro Immunol Infec 45:237–242
- 73.
Romanos M, Gerlach M, Warnke A, Schmitt J (2010) Association of attention-deficit/hyperactivity disorder and atopic eczema modified by sleep disturbance in a large population based sample. J Epidemiol Community Health 4:269–273
- 74.
Schmitt J, Apfelbacher C, Chen CM et al (2010) Infant-onset eczema in relation to mental health problems at age 10 years: results from a prospective birth control study (German Infant Nutrition Intervention plus). J Allergy Clin Immunol 125:404–410
- 75.
Schmitt J, Buske-Kirschbaum A, Roessner V (2010) Is atopic disease a risk factor for attention-deficit/hyperactivity disorder? a systematic review. Allergy 65:1506–1524
- 76.
Cuffe SP, Moore CG, McKeown R (2009) ADHD and health services utilization in the national health interview survey. J Atten Disord 12:330–340
- 77.
Cutuli JJ, Herbers JE, Rinaldi M, Masten AS, Orberg CN (2010) Asthma and behavior in homeless 4–7 year olds. Pediatrics 125:145–151
- 78.
Yuksel H, Sogut A, Yilmaz O (2008) Attention deficit and hyperactivity symptoms in children with asthma. J Asthma 45:545–547
- 79.
Boris M, Goldblatt A (2004) Pollen exposure as a cause for the deterioration of neurobehavioral function in children with autism and attention deficit hyperactive disorder: nasal pollen challenge. J Nutr Env Med 14:47–54
- 80.
Romanos M, Buske-Kirschbaum A, Fölster-Holst R, Gerlach M, Weidinger S, Schmitt J (2011) Itches and scratches—is there a link between eczema, ADHD, sleep disruption and food hypersensitivity? Allergy 66:1407–1409
- 81.
Bradstreet JJ, Smith S, Baral M, Rossignol DA (2010) Biomarker-guided interventions of clinically relevant conditions associated with autism spectrum disorders and attention deficit hyperactivity disorder. Altern Med Rev 15:15–32
- 82.
Dupont C, Barau E, Molkhou P, Raynaud F, Barbet JP, Dehennin L (1989) Food-induced alterations of intestinal permeability in children with cow’s milk-sensitive enteropathy and atopic dermatitis. JPGN 8:459–465
- 83.
Chida Y, Hamer M, Steptoe A (2008) A bidirectional relationship between psychosocial factors and atopic disorders: a systematic review and meta-analysis. Psychosom Med 70:102–116
- 84.
Chen M-H, Su T-P, Chen J-S et al (2013) Higher risk of mood disorders among adolescents with ADHD and asthma: A nationwide prospective study. J Affect Disord [Epub ahead of print]
- 85.
Chang HY, Seo J-H, Kim HY et al (2013) Allergic diseases in preschoolers are associated with psychological and behavioural problems. Allergy Asthma Immunol Res 5:315–321
- 86.
Wahn U (2007) World Allergy Organization: Disease summaries—the allergic march—introduction. http://www.worldallergy.org/professional/allergic_diseases_center/allergic_march/; accessed on 3 January 2014
- 87.
Halfon N, Newachek PW (2010) Evolving notions of childhood chronic illness. JAMA 303:665–666
- 88.
Stone KD, Prussin C, Metcalfe DD (2010) IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol 125:S73–S80
- 89.
van Beek AA, Knol EF, de Vos P et al (2012) Recent developments in basophil research: do basophils initiate and perpetuate type 2 T-helper cell responses? Int Arch Allergy Immunol 160:7–17
- 90.
Raison CL, Capuron L, Miller AH (2006) Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 27:24–31
- 91.
Mittleman BB, Castellanos FX, Jacobsen LK, Rapoport JL, Swedo SE, Shearer GM (1997) Cerebrospinal fluid cytokines in pediatric neuropsychiatric disease. J Immunol 159:2994–2999
- 92.
Entringer S, Claudia Buss C, Wadhwa PD (2010) Prenatal stress and developmental programming of human health and disease risk: concepts and integration of empirical findings. Curr Opin Endocrinol Diabetes Obes 17:507–516
- 93.
Warren RP, Odell JD, Warren WL, Burger RA, Maciulis A, Torres AR (1995) Is decreased blood plasma concentration of the complement c4b protein associated with attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatr 34:1009–1014
- 94.
Rout U, Mungan N, Dhossche D (2012) Presence of GAD65 autoantibodies in the serum of children with autism or ADHD. Eur Child Adolesc Psychiatr 21:141–147
- 95.
Ceylan M, Sener S, Bayraktar AC, Kavutcu M (2012) Changes in oxidative stress and cellular immunity serum markers in attention-deficit/hyperactivity disorder. Psychiatr Clin Neurosci 66:220–226
- 96.
Besser MJ, Ganor Y, Levite M (2005) Dopamine by itself activates either D2, D3 or D1/D5 dopaminergic receptors in normal human T-cells and triggers the selective secretion of either IL-10, TNF-α or both. J Neuroimmun 169:161–171
- 97.
Yukawa K, Iso H, Tanaka T et al (2005) Down-regulation of dopamine transporter and abnormal behaviour in STAT6-deficient mice. Int J Mol Med 15:819–825
- 98.
Peterson BS, Leckman JF, Tucker D et al (2000) Preliminary findings of antistreptococcal antibody titers and basal ganglia volumes in tic, obsessive-compulsive, and attention-deficit/hyperactivity disorders. Arch Gen Psychiatr 57:364–372
- 99.
Sanchez-Carpintero R, Albesa SA, Crespo N, Villoslada P, Narbona J (2009) A preliminary study of the frequency of anti-basal ganglia antibodies and streptococcal infection in attention deficit/hyperactivity disorder. J Neurol 256:1103–1108
- 100.
Toto M, Margari F, Simone M, et al (2012) Antibasal Ganglia Antibodies and Antistreptolysin O in Noncomorbid ADHD. J Atten Disord [Epub ahead of print]
- 101.
Nghiem DX, Kazimi N, Clydesdale G, Ananthaswamy HN, Kripke ML, Ullrich SE (2001) Ultraviolet A radiation suppresses an established immune response: implications for sunscreen design. J Invest Dermatol 117:1193–1199
- 102.
Milovanovic M, Heine G, Hallatschek W, Opitz B, Radbruch A, Worm M (2010) Vitamin D receptor binds to the ε germline gene promoter and exhibits transrepressive activity. J Allergy Clin Immunol 126:1016–1023
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Author information
Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Verlaet, A.A.J., Noriega, D.B., Hermans, N. et al. Nutrition, immunological mechanisms and dietary immunomodulation in ADHD. Eur Child Adolesc Psychiatry 23, 519–529 (2014). https://doi.org/10.1007/s00787-014-0522-2
Received:
Accepted:
Published:
Issue Date:
Keywords
- ADHD
- Dietary intervention
- Immune mechanism
- Immunomodulation
- Nutrition