The Role of Gut Microbiota-Brain Axis in Pathophysiology of ADHD: A Systematic Review

Abstract

Objective:

The main goal of this systematic review is to summarize evidences regarding alterations of microbial composition in ADHD cases and uncover underlying mechanisms.

Methods:

A comprehensive search was conducted on PubMed, Web of Science, and Scopus databases up to March 2021. All the observational studies including case-control, cross-sectional, and cohorts investigating the correlations between the gut microbiota and ADHD in both adults and children were included.

Results:

We found eight eligible studies. Enterococcus, Bifidobacterium, and Odoribacter were increased which may lead to impaired dopamine related functions in CNS. Moreover, decrease of Faecalibacterium frequency in ADHD could result in higher permeability and crossing of inflammatory cytokines. Regarding the short chain fatty acids-producing bacteria, Ruminococcaceae family decreased and Bacteroides uniformis and Bacteroides ovatus species increased.

Conclusion:

Gut microbiota correlation with ADHD and its underlying mechanisms could open new windows for developing novel therapies of ADHD by manipulating microbiota.

Keywords

ADHD gut-brain axis gut microbiota short chain fatty acids

Get full access to this article

View all access options for this article.

References

Aarts

Ederveen

T. H. A.

Naaijen

Zwiers

M. P.

Boekhorst

Timmerman

H. M.

Smeekens

S. P.

Netea

M. G.

Buitelaar

J. K.

Franke

van Hijum

S. A. F. T.

Arias Vasquez

(2017). Gut microbiome in ADHD and its relation to neural reward anticipation. PLoS One, 12(9), e0183509.

Agirman

Hsiao

E. Y.

(2021). SnapShot: The microbiota-gut-brain axis. Cell, 184(9), 2524–2524.e1.

American Psychiatric Association. (1980). Diagnostic and statistical manual of mental disorders (Vol. 3). American Psychiatric Association.

Angoorani

Hasani-Ranjbar

Soroush

A.-R.

Siadat

S. D.

Ejtahed

H.-S.

Sharifi

Arzaghi

S. M.

Fakhrzadeh

Larijani

(2021). The role of intestinal Microbiota in cognitive disorders. Journal of Mazandaran University of Medical Sciences, 31(193), 113–124.

Banerjee

Nandagopal

(2015). Does serotonin deficit mediate susceptibility to ADHD? Neurochemistry International, 82, 52–68.

Berg

Trollfors

Hugosson

Fernell

Svensson

(2002). Long-term follow-up of children with bacterial meningitis with emphasis on behavioural characteristics. European Journal of Pediatrics, 161(6), 330–336.

Braniste

Al-Asmakh

Kowal

Anuar

Abbaspour

Tóth

Korecka

Bakocevic

L. G.

Kundu

Gulyás

Halldin

Hultenby

Nilsson

Hebert

Volpe

B. T.

Diamond

Pettersson

(2014). The gut microbiota influences blood-brain barrier permeability in mice. Science Translational Medicine, 6(263), 263ra158.

Carabotti

Scirocco

Maselli

M. A.

Severi

(2015). The gut-brain axis: Interactions between enteric microbiota, central and enteric nervous systems. Annals of Gastroenterology, 28(2), 203–209.

Chang

Lichtenstein

Halldner

D’Onofrio

Serlachius

Fazel

Långström

Larsson

(2014). Stimulant ADHD medication and risk for substance abuse. Journal of Child Psychology and Psychiatry, 55(8), 878–885.

10.

Checa-Ros

Jeréz-Calero

Molina-Carballo

Campoy

Muñoz-Hoyos

(2021). Current evidence on the role of the gut microbiome in ADHD pathophysiology and therapeutic implications. Nutrients, 13(1), 249.

11.

Cheng

Han

Ding

Wen

Zhang

Cheng

Kafle

O. P.

Liang

Liu

Zhao

Zhang

(2020). Identifying psychiatric disorder-associated gut microbiota using microbiota-related gene set enrichment analysis. Briefings in Bioinformatics, 21(3), 1016–1022.

12.

Clayton

T. A.

(2012). Metabolic differences underlying two distinct rat urinary phenotypes, a suggested role for gut microbial metabolism of phenylalanine and a possible connection to autism. FEBS Letters, 586(7), 956–961.

13.

Costantini

Molinari

Farinon

Merendino

(2017). Impact of omega-3 fatty acids on the gut microbiota. International Journal of Molecular Sciences, 18(12), 2645.

14.

Costello

E. J.

Mustillo

Keeler

Angold

(2004). Prevalence of Psychiatric Disorders in Childhood and Adolescence. In Levin

B. L.

Petrila

Hennessy

K. D.

(Eds.), Mental health services: A public health perspective (pp. 111–128). Oxford University Press.

15.

Dam

S. A.

Mostert

J. C.

Szopinska-Tokov

J. W.

Bloemendaal

Amato

Arias-Vasquez

(2019). The role of the gut-brain axis in attention-deficit/hyperactivity disorder. Gastroenterology Clinics of North America, 48(3), 407–431.

16.

Ejtahed

H.-S.

Angoorani

Soroush

A. R.

Siadat

S. D.

Shirzad

Hasani-Ranjbar

Larijani

(2020). Our little friends with big roles: Alterations of the gut microbiota in thyroid disorders. Endocrine Metabolic & Immune Disorders - Drug Targets, 20(3), 344–350.

17.

Ejtahed

H.-S.

Soroush

A. R.

Angoorani

Larijani

Hasani-Ranjbar

(2016). Gut microbiota as a target in the pathogenesis of metabolic disorders: A new approach to novel therapeutic agents. Hormone and Metabolic Research, 48(6), 349–358.

18.

Fan

Wang

Fan

Liang

(2019). SCFA producing bacteria shape the subtype of ADHD in children. https://doi.org/10.21203/rs.2.16337/v1

19.

Faraone

S. V.

Biederman

Morley

C. P.

Spencer

T. J.

(2008). Effect of stimulants on height and weight: A review of the literature. Journal of the American Academy of Child and Adolescent Psychiatry, 47(9), 994–1009.

20.

Flint

H. J.

Scott

K. P.

Duncan

S. H.

Louis

Forano

(2012). Microbial degradation of complex carbohydrates in the gut. Gut Microbes, 3(4), 289–306.

21.

Gallo

E. F.

Posner

(2016). Moving towards causality in attention-deficit hyperactivity disorder: Overview of neural and genetic mechanisms. The Lancet Psychiatry, 3(6), 555–567.

22.

Garcia-Gutierrez

Narbad

Rodríguez

J. M.

(2020). Autism spectrum disorder associated with gut microbiota at immune, metabolomic, and neuroactive level. Frontiers in Neuroscience, 14, 578666.

23.

Gillies

Sinn

J. K. H.

Lad

S. S.

Leach

M. J.

Ross

M. J.

(2012). Polyunsaturated fatty acids (PUFA) for attention deficit hyperactivity disorder (ADHD) in children and adolescents. Cochrane Database of Systematic Reviews, 2012(7), CD007986. https://doi.org/10.1002/14651858.CD007986.

24.

Hasani-Ranjbar

Larijani

(2017). Human microbiome as an approach to personalized medicine. Alternative Therapies in Health and Medicine, 23(6), 8–9.

25.

Jiang

H. Y.

Zhou

Y. Y.

Zhou

G. L.

Y. C.

Yuan

X. H.

Ruan

(2018). Gut microbiota profiles in treatment-naïve children with attention deficit hyperactivity disorder. Behavioural Brain Research, 347, 408–413.

26.

Kim

K. M.

Lim

M. H.

Kwon

H. J.

Yoo

S. J.

Kim

E. J.

Kim

J. W.

Paik

K. C.

(2018). Associations between attention-deficit/hyperactivity disorder symptoms and dietary habits in elementary school children. Appetite, 127, 274–279.

27.

Maini Rekdal

Bess

E. N.

Bisanz

J. E.

Turnbaugh

P. J.

Balskus

E. P

. (2019). Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism. Science, 364(6445), eaau6323.

28.

L. L.

Wang

Y. Y.

Yang

Z. H.

Huang

Weng

Zeng

X. T.

(2020). Methodological quality (risk of bias) assessment tools for primary and secondary medical studies: What are they and which is better? Military Medical Research, 7(1), 7.

29.

Ming

Chen

Ray

Brewer

Kornitzer

Steer

R. A.

(2018). A gut feeling: A hypothesis of the role of the microbiome in attention-deficit/hyperactivity disorders. Child Neurology Open, 5, 2329048X18786799.

30.

Moher

Shamseer

Clarke

Ghersi

Liberati

Petticrew

Shekelle

Stewart

L. A.

(2015). Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Systematic Reviews, 4(1), 1–9.

31.

Montioli

Battini

Paiardini

Tolve

Bertoldi

Carducci

Leuzzi

Borri Voltattorni

(2019). A novel compound heterozygous genotype associated with aromatic amino acid decarboxylase deficiency: Clinical aspects and biochemical studies. Molecular Genetics and Metabolism, 127(2), 132–137.

32.

Paolicelli

R. C.

Bolasco

Pagani

Maggi

Scianni

Panzanelli

Giustetto

Ferreira

T. A.

Guiducci

Dumas

Ragozzino

Gross

C. T.

(2011). Synaptic pruning by microglia is necessary for normal brain development. Science, 333(6048), 1456–1458.

33.

Pärtty

Kalliomäki

Wacklin

Salminen

Isolauri

(2015). A possible link between early probiotic intervention and the risk of neuropsychiatric disorders later in childhood: A randomized trial. Pediatric Research, 77(6), 823–828.

34.

Peterson

Welch

Losos

Tugwell

P. J.

(2011). The Newcastle-Ottawa scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa Hospital Research Institute.

35.

Posner

Polanczyk

G. V.

Sonuga-Barke

(2020). Attention-deficit hyperactivity disorder. Lancet, 395, 450–462.

36.

Posner

Rauh

Gruber

Gat

Wang

Peterson

B. S.

(2013). Dissociable attentional and affective circuits in medication-naïve children with attention-deficit/hyperactivity disorder. Psychiatry Research Neuroimaging, 213(1), 24–30.

37.

Prehn-Kristensen

Zimmermann

Tittmann

Lieb

Schreiber

Baving

Fischer

(2018). Reduced microbiome alpha diversity in young patients with ADHD. PLoS One, 13(7), e0200728.

38.

Quévrain

Maubert

M. A.

Michon

Chain

Marquant

Tailhades

Miquel

Carlier

Bermúdez-Humarán

L. G.

Pigneur

Lequin

Kharrat

Thomas

Rainteau

Aubry

Breyner

Afonso

Lavielle

Grill

J. P.

Seksik

(2016). Identification of an anti-inflammatory protein from Faecalibacterium prausnitzii, a commensal bacterium deficient in Crohn’s disease. Gut, 65(3), 415–425.

39.

Rabiner

D. L.

(2013). Stimulant prescription cautions: Addressing misuse, diversion and malingering. Current Psychiatry Reports, 15(7), 375.

40.

Richarte

Sánchez-Mora

Corrales

Fadeuilhe

Vilar-Ribó

Arribas

Garcia

Rosales-Ortiz

S. K.

Arias-Vasquez

Soler-Artigas

Ribasés

Ramos-Quiroga

J. A.

(2021). Gut microbiota signature in treatment-naïve attention-deficit/hyperactivity disorder. Translational Psychiatry, 11(1), 382.

41.

Shaw

Eckstrand

Sharp

Blumenthal

Lerch

J. P.

Greenstein

Clasen

Evans

Giedd

Rapoport

J. L.

(2007). Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation. Proceedings of the National Academy of Sciences, 104(49), 19649–19654.

42.

Sherwin

Sandhu

K. V.

Dinan

T. G.

Cryan

J. F.

(2016). May the force be with you: The light and dark sides of the microbiota-gut-brain axis in neuropsychiatry. CNS Drugs, 30(11), 1019–1041.

43.

Shirvani Rad

Nikkhah

Orvatinia

Ejtahed

H. S.

Sarhangi

Jamaldini

S. H.

Khodayari

Aghaei Meybodi

H. R.

Hasanzad

. (2020). Gut microbiota: A perspective of precision medicine in endocrine disorders. Journal of Diabetes & Metabolic Disorders, 19, 1827–1834.

44.

Shirvanirad

Nikkhah

Orvatinia

M. M.

Ejtahed

H.-S.

Sarhangi

Meybodi

H. R. A.

Hasanzad

(2021). The microbiome in precision medicine: A new approach to cancer treatment. Journal of Mazandaran University of Medical Sciences, 31(193), 21–37.

45.

Simon

Czobor

Bálint

Mészáros

Bitter

(2009). Prevalence and correlates of adult attention-deficit hyperactivity disorder: Meta-analysis. The British Journal of Psychiatry, 194(3), 204–211.

46.

Stevens

A. J.

Purcell

R. V.

Darling

K. A.

Eggleston

M. J. F.

Kennedy

M. A.

Rucklidge

J. J.

(2019). Human gut microbiome changes during a 10 week randomised control trial for micronutrient supplementation in children with attention deficit hyperactivity disorder. Scientific Reports, 9(1), 10128.

47.

Sukmajaya

A. C.

Lusida

M. I.

Setiawati

(2021). Systematic review of gut microbiota and attention-deficit hyperactivity disorder (ADHD). Annals of General Psychiatry, 20(1), 12.

48.

Szopinska-Tokov

Dam

Naaijen

Konstanti

Rommelse

Belzer

Buitelaar

Franke

Aarts

Arias Vasquez

(2020). Investigating the gut microbiota composition of individuals with attention-deficit/hyperactivity disorder and association with symptoms. Microorganisms, 8(3), 406.

49.

Wang

L.-J.

Yang

C. Y.

Chou

W. J.

Lee

M. J.

Chou

M. C.

Kuo

H. C.

Yeh

Y. M.

Lee

S. Y.

Huang

L. H.

S. C.

(2020). Gut microbiota and dietary patterns in children with attention-deficit/hyperactivity disorder. European Child & Adolescent Psychiatry, 29(3), 287–297.

50.

Wan

W. R.

Zhang

Sun

Y. L.

Wang

Yang

(2020). Case-control study of the effects of gut microbiota composition on neurotransmitter metabolic pathways in children with attention deficit hyperactivity disorder. Frontiers in Neuroscience, 14, 127.

51.

Wong

M.-L.

Inserra

Lewis

M. D.

Mastronardi

C. A.

Leong

Choo

Kentish

Xie

Morrison

Wesselingh

S. L.

Rogers

G. B.

Licinio

(2016). Inflammasome signaling affects anxiety- and depressive-like behavior and gut microbiome composition. Molecular Psychiatry, 21(6), 797–805.

52.

Jerse

A. E.

(2006). α-2,3-Sialyltransferase enhances Neisseria gonorrhoeae survival during experimental murine genital tract infection. Infection and Immunity, 74(7), 4094–4103.