Associations of the gut microbiome and inflammatory markers with mental health symptoms: a cross-sectional study on Danish adolescents

Faraone, S. V. et al. The world federation of ADHD international consensus statement: 208 evidence-based conclusions about the disorder. Neurosci. Biobehav. Rev. 128, 789–818 (2021).

PubMed 
PubMed Central 
MATH 

Google Scholar 

Mehta, T. R., Monegro, A., Nene, Y., Fayyaz, M. & Bollu, P. C. Neurobiology of ADHD: a review. Curr. Dev. Disord Rep. 6, 235–240 (2019).

Google Scholar 

Aarts, E. et al. Gut Microbiome in ADHD and its relation to neural reward anticipation. PLOS ONE 12, e0183509 (2017).

PubMed 
PubMed Central 
MATH 

Google Scholar 

Long, L. et al. The impact of integrating a low-lectin diet with traditional ADHD treatments on gut microbiota composition and symptom improvement in children—a cohort study. Neuropsychiatr. Dis. Treat. 20, 535–549 (2024).

PubMed 
PubMed Central 
MATH 

Google Scholar 

Prehn-Kristensen, A. et al. Reduced Microbiome alpha diversity in young patients with ADHD. PLOS ONE 13, e0200728 (2018).

PubMed 
PubMed Central 

Google Scholar 

Wan, L. et al. Case-control study of the effects of gut microbiota composition on neurotransmitter metabolic pathways in children with attention deficit hyperactivity disorder. Front. Neurosci. 14, 1456 (2020).

Wang, N. et al. Metagenomic analysis reveals difference of gut microbiota in ADHD. J. Atten. Disord. 28, 872–879 (2024).

PubMed 
MATH 

Google Scholar 

Berg, G. et al. Microbiome definition re-visited: old concepts and new challenges. Microbiome 8, 103 (2020).

PubMed 
PubMed Central 
MATH 

Google Scholar 

Góralczyk-Bińkowska, A., Szmajda-Krygier, D. & Kozłowska, E. The microbiota–gut–brain axis in psychiatric disorders. Int. J. Mol. Sci. 23, 11245 (2022).

PubMed 
PubMed Central 

Google Scholar 

Logan, A. C., Jacka, F. N. & Prescott, S. L. Immune-microbiota interactions: dysbiosis as a global health issue. Curr. Allergy Asthma Rep. 16, 13 (2016).

PubMed 
MATH 

Google Scholar 

Anand, D., Colpo, G. D., Zeni, G., Zeni, C. P. & Teixeira, A. L. Attention-deficit/hyperactivity disorder and inflammation: what does current knowledge tell Us? A systematic review. Front. Psychiatry 8, 228 (2017).

PubMed 
PubMed Central 
MATH 

Google Scholar 

Kaas, T. H. et al. Association between childhood asthma and attention deficit hyperactivity or autism spectrum disorders: a systematic review with meta-analysis. Clin. Exp. Allergy J. Br. Soc. Allergy Clin. Immunol. 51, 228–252 (2021).

MATH 

Google Scholar 

Saccaro, L. F., Schilliger, Z., Perroud, N. & Piguet, C. Inflammation, anxiety, and stress in attention-deficit/hyperactivity disorder. Biomedicines 9, 1313 (2021).

CAS 
PubMed 
PubMed Central 

Google Scholar 

Schnorr, I. et al. Inflammatory biotype of ADHD is linked to chronic stress: a data-driven analysis of the inflammatory proteome. Transl Psychiatry 14, 1–14 (2024).

MATH 

Google Scholar 

Checa-Ros, A., Jeréz-Calero, A., Molina-Carballo, A., Campoy, C. & Muñoz-Hoyos, A. Current evidence on the role of the gut Microbiome in ADHD pathophysiology and therapeutic implications. Nutrients 13, 249 (2021).

Wang, L. J. et al. Gut microbiota and plasma cytokine levels in patients with attention-deficit/hyperactivity disorder. Transl Psychiatry 12, 1–9 (2022).

Google Scholar 

Sukmajaya, A. C., Lusida, M. I., Setiawati, Y. & Soetjipto & Systematic review of gut microbiota and attention-deficit hyperactivity disorder (ADHD). Ann. Gen. Psychiatry 20, 12 (2021).

PubMed 
PubMed Central 
MATH 

Google Scholar 

Teepe, G. W. et al. Development of a digital biomarker and intervention for subclinical depression: study protocol for a longitudinal waitlist control study. BMC Psychol. 11, 186 (2023).

PubMed 
PubMed Central 
MATH 

Google Scholar 

Loyer Carbonneau, M., Demers, M., Bigras, M. & Guay, M. C. Meta-analysis of sex differences in ADHD symptoms and associated cognitive deficits. J. Atten. Disord. 25, 1640–1656 (2021).

PubMed 

Google Scholar 

Kim, Y. S., Unno, T., Kim, B. Y. & Park, M. S. Sex differences in gut microbiota. World J. Mens Health 38, 48–60 (2020).

PubMed 
MATH 

Google Scholar 

Chang, E., Varghese, M. & Singer, K. Gender and sex differences in adipose tissue. Curr. Diab. Rep. 18, 69 (2018).

PubMed 
PubMed Central 
MATH 

Google Scholar 

Khera, A. et al. Sex differences in the relationship between C-reactive protein and body fat. J. Clin. Endocrinol. Metab. 94, 3251–3258 (2009).

CAS 
PubMed 
PubMed Central 
MATH 

Google Scholar 

Bisgaard, H. The Copenhagen prospective study on asthma in childhood (COPSAC): design, rationale, and baseline data from a longitudinal birth cohort study. Ann. Allergy Asthma Immunol. 93, 381–389 (2004).

PubMed 
MATH 

Google Scholar 

Kessler, R. C. et al. The world health organization adult ADHD self-report scale (ASRS): a short screening scale for use in the general population. Psychol. Med. 35, 245–256 (2005).

PubMed 
MATH 

Google Scholar 

Kessler, R. C. et al. Validity of the world health organization adult ADHD Self-Report scale (ASRS) screener in a representative sample of health plan members. Int. J. Methods Psychiatr. Res. 16, 52–65 (2007).

PubMed 
PubMed Central 
MATH 

Google Scholar 

NovoPsych Adult ADHD Self-Report Scale (ASRS). https://novopsych.com.au/assessments/diagnosis/adult-adhd-self-report-scale-asrs/ (2021).

Stanton, K., Forbes, M. K. & Zimmerman, M. Distinct dimensions defining the adult ADHD Self-Report scale: implications for assessing inattentive and hyperactive/impulsive symptoms. Psychol. Assess. 30, 1549–1559 (2018).

PubMed 

Google Scholar 

Ryan, D. & Sadek, J. Risk and adversity factors in adult patients with comorbid attention deficit hyperactivity disorder (ADHD), binge eating disorder (BED), and borderline personality disorder (BPD): a naturalistic exploratory study. Brain Sci. 13, 669 (2023).

PubMed 
PubMed Central 

Google Scholar 

Sonnby, K. et al. Validation of the world health organization adult ADHD self-report scale for adolescents. Nord J. Psychiatry 69, 216–223 (2015).

PubMed 

Google Scholar 

Hoeffding, L. et al. Socio-demographic characteristics of adults with self-reported ADHD symptoms in a Danish population of 12,415 blood donors. J. Psychiatry Behav. Sci. 1, 1456 (2018).

Antony, M. M., Bieling, P. J., Cox, B. J., Enns, M. W. & Swinson, R. P. Psychometric properties of the 42-item and 21-item versions of the depression anxiety stress scales in clinical groups and a community sample. Psychol. Assess. 10, 176–181 (1998).

Google Scholar 

Osman, A. et al. The depression anxiety stress Scales—21 (DASS-21): further examination of dimensions, scale reliability, and correlates. J. Clin. Psychol. 68, 1322–1338 (2012).

PubMed 
MATH 

Google Scholar 

Al-Dassean, K. A. & Murad, O. S. Factor structure and psychometric properties of the Jordanian version of the depression anxiety stress scale (DASS-21). Neuropsychopharmacol. Rep. 44, 447–456 (2024).

PubMed 
PubMed Central 
MATH 

Google Scholar 

Coker, A. O., Coker, O. O. & Sanni, D. Psychometric properties of the 21-item depression anxiety stress scale (DASS-21). Afr. Res. Rev. 12, 135–142 (2018).

MATH 

Google Scholar 

Evans, L., Haeberlein, K., Chang, A. & Handal, P. Convergent validity and preliminary cut-off scores for the anxiety and depression subscales of the DASS-21 in US adolescents. Child. Psychiatry Hum. Dev. 52, 579–585 (2021).

PubMed 

Google Scholar 

Stroeve, J. H. M., van Wietmarschen, H., Kremer, B. H. A., van Ommen, B. & Wopereis, S. Phenotypic flexibility as a measure of health: the optimal nutritional stress response test. Genes Nutr. 10, 13 (2015).

PubMed 
PubMed Central 

Google Scholar 

Ebrahimi, P. et al. Systemic inflammation during fasting and postprandial States: a comprehensive study of key determinants in a deeply characterized cohort of young adults. https://doi.org/10.1101/2024.08.30.24312659 (2024).

Connelly, M. A., Otvos, J. D., Shalaurova, I., Playford, M. P. & Mehta, N. N. GlycA, a novel biomarker of systemic inflammation and cardiovascular disease risk. J. Transl Med. 15, 219 (2017).

PubMed 
PubMed Central 

Google Scholar 

Fuertes-Martín, R., Correig, X., Vallvé, J. C. & Amigó, N. Human serum/plasma glycoprotein analysis by 1H-NMR, an emerging method of inflammatory assessment. J. Clin. Med. 9, 354 (2020).

PubMed 
PubMed Central 

Google Scholar 

Gialluisi, A. et al. Lifestyle and biological factors influence the relationship between mental health and low-grade inflammation. Brain Behav. Immun. 85, 4–13 (2020).

CAS 
PubMed 

Google Scholar 

Gustafsson, H. C. et al. Evaluation of maternal inflammation as a marker of future offspring ADHD symptoms: a prospective investigation. Brain Behav. Immun. 89, 350–356 (2020).

CAS 
PubMed 
PubMed Central 
MATH 

Google Scholar 

Rosenberg, J. B. et al. Maternal inflammation during pregnancy is associated with risk of ADHD in children at age 10. Brain Behav. Immun. 115, 450–457 (2024).

PubMed 
MATH 

Google Scholar 

najoshi. sickle – A windowed adaptive trimming tool for FASTQ files using quality. https://github.com/najoshi/sickle (2023).

Milanese, A. et al. Microbial abundance, activity and population genomic profiling with mOTUs2. Nat. Commun. 10, 1014 (2019).

ADS 
PubMed 
PubMed Central 
MATH 

Google Scholar 

Franzosa, E. A. et al. Species-level functional profiling of metagenomes and metatranscriptomes. Nat. Methods 15, 962–968 (2018).

CAS 
PubMed 
PubMed Central 
MATH 

Google Scholar 

Caspi, R. et al. The metacyc database of metabolic pathways and enzymes—a 2019 update. Nucleic Acids Res. 48, D445–D453 (2020).

CAS 
PubMed 
MATH 

Google Scholar 

Bull-Larsen, S. & Mohajeri, M. H. The potential influence of the bacterial microbiome on the development and progression of ADHD. Nutrients 11, 2805 (2019).

CAS 
PubMed 
PubMed Central 
MATH 

Google Scholar 

Davidson, M., Rashidi, N., Nurgali, K. & Apostolopoulos, V. The role of Tryptophan metabolites in neuropsychiatric disorders. Int. J. Mol. Sci. 23, 9968 (2022).

CAS 
PubMed Central 

Google Scholar 

Dinu, L. M., Phattharakulnij, N. & Dommett, E. J. Tryptophan modulation in individuals with attention deficit hyperactivity disorder: a systematic review. J. Neural Transm. 129, 361–377 (2022).

CAS 
PubMed 
MATH 

Google Scholar 

O’Mahony, S. M., Clarke, G., Borre, Y. E., Dinan, T. G. & Cryan, J. F. Serotonin, Tryptophan metabolism and the brain-gut-microbiome axis. Behav. Brain Res. 277, 32–48 (2015).

PubMed 

Google Scholar 

Cortese, S. The association between ADHD and obesity: intriguing, progressively more investigated, but still puzzling. Brain Sci. 9, 256 (2019).

PubMed 
PubMed Central 
MATH 

Google Scholar 

Cortese, S. et al. Association between ADHD and obesity: a systematic review and meta-analysis. Am. J. Psychiatry 173, 34–43 (2016).

PubMed 
MATH 

Google Scholar 

Kopp, W. How Western diet and lifestyle drive the pandemic of obesity and civilization diseases. Diabetes Metab. Syndr. Obes. Targets Ther. 12, 2221–2236 (2019).

CAS 
MATH 

Google Scholar 

Gao, X. et al. Body mass index differences in the gut microbiota are gender specific. Front. Microbiol. 9, 1456 (2018).

Lasselin, J. & Capuron, L. Chronic low-grade inflammation in metabolic disorders: relevance for behavioral symptoms. Neuroimmunomodulation 21, 95–101 (2014).

CAS 
PubMed 

Google Scholar 

Skogli, E. W., Teicher, M. H., Andersen, P. N., Hovik, K. T. & Øie, M. ADHD in girls and boys—gender differences in co-existing symptoms and executive function measures. BMC Psychiatry. 13, 298 (2013).

Dietert, R. R. Maternal and childhood asthma: risk factors, interactions, and ramifications. Reprod. Toxicol. 32, 198–204 (2011).

CAS 
PubMed 
MATH 

Google Scholar 

R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing. https://www.R-project.org/ (2022).

Kuhn, M. Building predictive models in R using the caret package. J. Stat. Softw. 28, 1–26 (2008).

MATH 

Google Scholar 

Kuhn, M., Jackson, S. & Cimentada, J. Correlations R. https://CRAN.R-project.org/package=corrr (2022).

McMurdie, P. J. & Holmes, S. Phyloseq: an R package for reproducible interactive analysis and graphics of Microbiome census data. PLoS ONE 8, e61217 (2013).

ADS 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Oksanen, J. et al. vegan: community ecology package. https://CRAN.R-project.org/package=vegan (2022).

Stokholm, J. rabuplot: Relative Abundance Plot (2023).

Yoshida, K. & Bartel, A. Tableone: create ‘table 1’ to describe baseline characteristics with or without propensity score weights (2022). https://CRAN.R-project.org/package=tableone.

Thorsteinsdottir, S. et al. Genetic, clinical, and environmental factors associated with persistent atopic dermatitis in childhood. JAMA Dermatol. 155, 50–57 (2019).

PubMed 

Google Scholar 

Vos, T. et al. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the global burden of disease study 2019. Lancet 396, 1204–1222 (2020).

MATH 

Google Scholar 

Brevik, E. J., Lundervold, A. J., Haavik, J. & Posserud, M. B. Validity and accuracy of the adult Attention-Deficit/Hyperactivity disorder (ADHD) Self-Report scale (ASRS) and the Wender Utah rating scale (WURS) symptom checklists in discriminating between adults with and without ADHD. Brain Behav. 10, e01605 (2020).

PubMed 
PubMed Central 

Google Scholar 

Nieto, I., Robles, E. & Vazquez, C. Self-reported cognitive biases in depression: a meta-analysis. Clin. Psychol. Rev. 82, 101934 (2020).

PubMed 
MATH 

Google Scholar 

Conlon, M. A. & Bird, A. R. The impact of diet and lifestyle on gut microbiota and human health. Nutrients 7, 17–44 (2014).

PubMed 
PubMed Central 
MATH 

Google Scholar 

Del-Ponte, B., Quinte, G. C., Cruz, S., Grellert, M. & Santos, I. S. Dietary patterns and attention deficit/hyperactivity disorder (ADHD): a systematic review and meta-analysis. J. Affect. Disord. 252, 160–173 (2019).

PubMed 

Google Scholar 

Gelman, A. & Carlin, J. Beyond power calculations: assessing type S (Sign) and type M (Magnitude) errors. Perspect. Psychol. Sci. 9, 641–651 (2014).

PubMed 
MATH 

Google Scholar 

Tipton, E., Hallberg, K., Hedges, L. V. & Chan, W. Implications of small samples for generalization: adjustments and rules of thumb. Eval. Rev. 41, 472–505 (2017).

PubMed 
MATH 

Google Scholar 

Oades, R. D., Myint, A. M., Dauvermann, M. R., Schimmelmann, B. G. & Schwarz, M. J. Attention-deficit hyperactivity disorder (ADHD) and glial integrity: an exploration of associations of cytokines and kynurenine metabolites with symptoms and attention. Behav. Brain Funct. 6, 32 (2010).

PubMed 
PubMed Central 

Google Scholar 

Miller, A. H., Haroon, E., Raison, C. L. & Felger, J. C. Cytokine targets in the brain: impact on neurotransmitters and neurocircuits. Depress. Anxiety 30, 297–306 (2013).

CAS 
PubMed 
MATH 

Google Scholar 

Mathee, K., Cickovski, T., Deoraj, A., Stollstorff, M. & Narasimhan, G. The gut Microbiome and neuropsychiatric disorders: implications for attention deficit hyperactivity disorder (ADHD). J. Med. Microbiol. 69, 14–24 (2020).

CAS 
PubMed 

Google Scholar 

Darwish, A. H., Elgohary, T. M. & Nosair, N. A. Serum interleukin-6 level in children with attention-deficit hyperactivity disorder (ADHD). J. Child. Neurol. 34, 61–67 (2019).

PubMed 

Google Scholar 

Boulanger-Bertolus, J., Pancaro, C. & Mashour, G. A. Increasing role of maternal immune activation in neurodevelopmental disorders. Front. Behav. Neurosci. 12, (2018).

Knuesel, I. et al. Maternal immune activation and abnormal brain development across CNS disorders. Nat. Rev. Neurol. 10, 643–660 (2014).

CAS 
PubMed 

Google Scholar 

Aria, F. et al. Brain structural and functional alterations in mice prenatally exposed to LPS are only partially rescued by anti-inflammatory treatment. Brain Sci. 10, 620 (2020).

CAS 
PubMed 
PubMed Central 

Google Scholar 

Onore, C. E., Schwartzer, J. J., Careaga, M., Berman, R. F. & Ashwood, P. Maternal immune activation leads to activated inflammatory macrophages in offspring. Brain Behav. Immun. 38, 220–226 (2014).

CAS 
PubMed 
PubMed Central 

Google Scholar 

Yokomizo, H. et al. Maternal high-fat diet induces insulin resistance and deterioration of pancreatic β-cell function in adult offspring with sex differences in mice. Am. J. Physiol. -Endocrinol. Metab. 306, E1163–E1175 (2014).

CAS 
PubMed 
MATH 

Google Scholar 

Plant, D. T., Pawlby, S., Sharp, D., Zunszain, P. A. & Pariante, C. M. Prenatal maternal depression is associated with offspring inflammation at 25 years: a prospective longitudinal cohort study. Transl Psychiatry 6, e936–e936 (2016).

CAS 
PubMed 
PubMed Central 

Google Scholar 

Kittel-Schneider, S. et al. Non-mental diseases associated with ADHD across the lifespan: fidgety Philipp and Pippi Longstocking at risk of Multimorbidity?? Neurosci. Biobehav Rev. 132, 1157–1180 (2022).

PubMed 
MATH 

Google Scholar 

Björk, A. et al. Health, lifestyle habits, and physical fitness among adults with ADHD compared with a random sample of a Swedish general population. Soc. Health Vulnerability 9, 1553916 (2018).

Google Scholar 

Ma, W. et al. Dietary fiber intake, the gut microbiome, and chronic systemic inflammation in a cohort of adult men. Genome Med. 13, 102 (2021).

CAS 
PubMed 
PubMed Central 
MATH 

Google Scholar 

Bodden, D. H. M., van den Heuvel, M. W. H., Engels, R. C. M. E. & Dirksen, C. D. Societal costs of subclinical depressive symptoms in Dutch adolescents: a cost-of-illness study. J. Child. Psychol. Psychiatry 63, 771–780 (2022).

PubMed 

Google Scholar 

Banerjee, E. & Nandagopal, K. Does serotonin deficit mediate susceptibility to ADHD? Neurochem Int. 82, 52–68 (2015).

CAS 
PubMed 
MATH 

Google Scholar 

Hinshaw, S. P., Nguyen, P. T., O’Grady, S. M. & Rosenthal, E. A. Annual research review: attention-deficit/hyperactivity disorder in girls and women: underrepresentation, longitudinal processes, and key directions. J. Child. Psychol. Psychiatry. 63, 484–496 (2022).

PubMed 

Google Scholar 

Botha, F., Morris, R. W., Butterworth, P. & Glozier, N. Generational differences in mental health trends in the twenty-first century. Proc. Natl. Acad. Sci. 120, e2303781120 (2023).

Buźniak, A., Woropay-Hordziejewicz, N. A., Bereznowska, A. & Atroszko, P. A. Alarmingly high prevalence and lack of gender differences in ADHD among high school students: screening for ADHD with ASRS among adolescents and working adults. Curr. Probl. Psychiatry. 23, 237–245 (2022).

Google Scholar 

Lee, G. J., Fife, K., Fought, L., Fowler, T. & Suhr, J. Social media use relates to beliefs about attention-deficit/hyperactivity disorder (ADHD) among emerging adults. J. Int. Neuropsychol. Soc. 29, 642–643 (2023).

Google Scholar 

Abdelnour, E., Jansen, M. O. & Gold, J. A. ADHD diagnostic trends: increased recognition or overdiagnosis? Mo Med. 119, 467–473 (2022).

PubMed 
PubMed Central 

Google Scholar 

Fried, E. I. Studying mental health problems as systems, not syndromes. Curr. Dir. Psychol. Sci. 31, 500–508 (2022).

MATH 

Google Scholar