Investigation of Plasma TMAO Levels in Children and Adolescents with ADHD: A Cross-Sectional Study

Year 2025, Volume: 35 Issue: 3, 435 - 441, 30.06.2025

Ahmet Güleç , Serhat Türkoğlu , Ramazan Kocabaş , Mustafa Tezcan

https://doi.org/10.54005/geneltip.1592267

Abstract

Investigation of Plasma TMAO Levels in Children and Adolescents with ADHD: A Cross-Sectional Study
Abstract
Background/Aims:
Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent neurodevelopmental disorder among children and adolescents. Emerging evidence suggests a potential connection between gut microbiota-derived metabolites, such as Trimethylamine N-oxide (TMAO), and neuropsychiatric disorders. This study aims to examine plasma TMAO levels in children and adolescents with ADHD and to explore the relationship between TMAO levels and the severity of ADHD symptoms.
Methods:
This cross-sectional study included 96 participants aged 7 to 15 years, comprising 50 patients diagnosed with ADHD and 46 healthy controls. Plasma TMAO levels were determined using the Enzyme-Linked Immunosorbent Assay (ELISA) method. The severity of ADHD symptoms was assessed using the T-DSM-IV-TR scale.
Results:
Plasma TMAO levels were significantly higher in the ADHD group compared to the control group (p=0.02). A positive correlation was identified between plasma TMAO levels and total T-DSM-IV-TR scores (p<0.001), indicating that higher TMAO levels are associated with increased severity of ADHD symptoms. However, no significant correlations were observed between TMAO levels and other subscale scores.
Conclusions:
This study indicates that elevated plasma TMAO levels in children and adolescents with ADHD may reflect a biochemical characteristic of the disorder. Additionally, the association between TMAO levels and ADHD symptom severity suggests that TMAO might play a role in the pathophysiology of ADHD.

Keywords

ADHD , Trimethylamine N-oxide , gut microbiome , neurotoxicity , child and adolescent psychiatry

DEHB'li Çocuk ve Ergenlerde Plazma TMAO Seviyelerinin İncelenmesi: Kesitsel Bir Çalışma

Abstract

Giriş/Amaç:
Dikkat Eksikliği ve Hiperaktivite Bozukluğu (DEHB), çocuk ve ergenlerde yaygın görülen nörogelişimsel bir rahatsızlıktır. Son araştırmalar, bağırsak mikrobiyotası kaynaklı metabolitler, özellikle Trimethylamine N-oxide (TMAO), ile nöropsikiyatrik hastalıklar arasında potansiyel bir bağlantı olduğunu öne sürmektedir. Bu çalışma, DEHB’li çocuk ve ergenlerde plazma TMAO seviyelerini değerlendirmeyi ve TMAO seviyeleri ile DEHB semptomlarının şiddeti arasındaki ilişkiyi incelemeyi amaçlamaktadır.

Yöntemler:
Bu kesitsel çalışma, 7-15 yaşları arasında 96 katılımcıyı içermiştir; bunların 50’si DEHB tanısı almış hastalardan, 46’sı ise sağlıklı kontrol grubundan oluşmaktadır. Plazma TMAO seviyeleri, Enzim Bağlı İmmünosorbent Testi (ELISA) yöntemiyle ölçülmüştür. DEHB semptomlarının şiddeti, T-DSM-IV-TR ölçeği kullanılarak değerlendirilmiştir.

Bulgular:
Plazma TMAO seviyeleri, DEHB grubunda kontrol grubuna kıyasla anlamlı derecede daha yüksek bulunmuştur (p=0.02). Ayrıca, plazma TMAO seviyeleri ile toplam T-DSM-IV-TR puanları arasında pozitif bir korelasyon tespit edilmiştir (p<0.001). Bu bulgu, daha yüksek TMAO seviyelerinin daha şiddetli DEHB semptomları ile ilişkili olduğunu göstermektedir. Ancak, TMAO seviyeleri ile diğer alt ölçek puanları arasında anlamlı bir ilişki bulunamamıştır.

Sonuç:
Bu çalışma, DEHB’li çocuk ve ergenlerde yüksek plazma TMAO seviyelerinin, bozukluğun biyokimyasal özelliklerini yansıtabileceğini göstermektedir. Ayrıca, TMAO seviyeleri ile DEHB semptomlarının şiddeti arasındaki ilişki, TMAO’nun DEHB’nin fizyopatolojisinde potansiyel bir rol oynayabileceğini düşündürmektedir.

Keywords

DEHB , Trimetilamin N-oksit , bağırsak mikrobiyomu , nörotoksisite , çocuk ve ergen psikiyatrisi

References

• 1. Childress AC, Berry SA. Pharmacotherapy of attention-deficit hyperactivity disorder in adolescents. Drugs. 2012;72(3):309-325.
• 2. El-Sadek A, Soliman D, Elbakry S, Behiry E, Omran H. Clinical evaluation of Latrophilin 3 (LPHN3) gene in children with attention deficit hyperactivity disorder (ADHD). Braz J Anal Sci. 2021;6(2):129-132.
• 3. Wu J, Xiao H, Sun H, Zou L, Zhu LQ. Role of dopamine receptors in ADHD: a systematic meta-analysis. Mol Neurobiol. 2012;45(3):605-620.
• 4. Shaw P, Rabin C. New insights into attention-deficit/hyperactivity disorder using structural neuroimaging. Curr Psychiatry Rep. 2009;11(5):393-398.
• 5. Prehn-Kristensen A, Zimmermann A, Tittmann L, et al. Reduced microbiome alpha diversity in young patients with ADHD. PLoS One. 2018;13(7):e0200728.
• 6. Slob EM, Brew BK, Vijverberg SJ, et al. Early-life antibiotic use and risk of attention-deficit hyperactivity disorder and autism spectrum disorder: results of a discordant twin study. Int J Epidemiol. 2021;50(2):475-484.
• 7. Bundgaard-Nielsen C, Knudsen J, Leutscher PD, et al. Gut microbiota profiles of autism spectrum disorder and attention-deficit/hyperactivity disorder: A systematic literature review. Gut Microbes. 2020;11(5):1172-1187.
• 8. Forsythe P, Kunze WA. Voices from within: gut microbes and the CNS. Cell Mol Life Sci. 2013;70(1):55-69.
• 9. Taş E, Ülgen KO. Understanding the ADHD-Gut Axis by Metabolic Network Analysis. Metabolites. 2023;13(5):612.
• 10. Aarts E, Ederveen THA, Naaijen J, et al. Gut microbiome in ADHD and its relation to neural reward anticipation. PLoS One. 2017;12(9):e0183509.
• 11. Bundgaard-Nielsen C, Knudsen J, Leutscher PDC, et al. Gut microbiota profiles of autism spectrum disorder and attention-deficit/hyperactivity disorder: A systematic literature review. Gut Microbes. 2020;11(5):1172-1187.
• 12. Janeiro MH, Ramírez MJ, Milagro FI, Martínez JA, Solas M. Implication of trimethylamine N-oxide (TMAO) in disease: Potential biomarker or new therapeutic target. Nutrients. 2018;10(10):1398.
• 13. Açıkel SB, Kara A, Bağcı Z, Can Ü. Serum trimethylamine N-oxide and lipopolysaccharide-binding protein levels among children diagnosed with autism spectrum disorder. Int J Dev Neurosci. 2023;83(6):571-577.
• 14. Craciun S, Balskus EP. Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme. Proc Natl Acad Sci U S A. 2012;109(52):21307-21312.
• 15. Quan L, Yi J, Zhao Y, et al. Plasma trimethylamine N-oxide, a gut microbe-generated phosphatidylcholine metabolite, is associated with autism spectrum disorders. Neurotoxicology. 2020;76:93-98.
• 16. Zixin Y, Lulu C, Xiangchang Z, et al. TMAO as a potential biomarker and therapeutic target for chronic kidney disease: A review. Front Pharmacol. 2022;13:929262.
• 17. Tu R, Xia J. Stroke and vascular cognitive impairment: The role of intestinal microbiota metabolite TMAO. Curr Neuropharmacol. 2023;21(8):1767-1779.
• 18. Vernetti L, Gough A, Baetz N, et al. Functional coupling of human microphysiology systems: intestine, liver, kidney proximal tubule, blood-brain barrier, and skeletal muscle. Sci Rep. 2017;7:42296.
• 19. Del Rio D, Zimetti F, Caffarra P, et al. The gut microbial metabolite trimethylamine-N-oxide is present in human cerebrospinal fluid. Nutrients. 2017;9(10):1053.
• 20. Qiao CM, Quan W, Zhou Y, et al. Orally induced high serum level of trimethylamine N-oxide worsened glial reaction and neuroinflammation on MPTP-induced acute Parkinson's disease model mice. Mol Neurobiol. 2023;60(9):5137-5154.
• 21. Soltani Khaboushan A, Yazdanpanah N, Rezaei N. Neuroinflammation and proinflammatory cytokines in epileptogenesis. Mol Neurobiol. 2022;59(3):1724-1743.
• 22. Chen AQ, Fang Z, Chen XL, et al. Microglia-derived TNF-α mediates endothelial necroptosis aggravating blood-brain barrier disruption after ischemic stroke. Cell Death Dis. 2019;10(7):487.
• 23. Vázquez-González D, et al. A potential role for neuroinflammation in ADHD. Adv Exp Med Biol. 2023;1411:327-356.
• 24. Kerekes N, Sánchez-Pérez AM, Landry M. Neuroinflammation as a possible link between attention-deficit/hyperactivity disorder (ADHD) and pain. Med Hypotheses. 2021;157:110717.
• 25. Gao Q, Wang Y, Wang X, et al. Decreased levels of circulating trimethylamine N-oxide alleviate cognitive and pathological deterioration in transgenic mice: a potential therapeutic approach for Alzheimer's disease. Aging (Albany NY). 2019;11(19):8642-8663.
• 26. Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P, et al. 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. 1997;36(7):980-988.
• 27. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed (DSM-5). Arlington, VA: American Psychiatric Publishing; 2013.
• 28. Gökler B, Ünal F, Pehlivantürk B, Çengel Kültür SE, Akdemir D, Taner Y. Reliability and validity of schedule for affective disorders and schizophrenia for school-age children-present and lifetime version-Turkish version (K-SADS-PL-T). Turk J Child Adolesc Ment Health. 2004;11(3):109-116.
• 29. Ercan E, Amado S, Somer O, Çikoğlu S. Dikkat eksikliği hiperaktivite bozukluğu ve yıkıcı davranış bozuklukları için bir test bataryası geliştirme çalışması. Çocuk ve Gençlik Ruh Sağlığı Dergisi. 2001;8(3):132-144.
• 30. Turgay A. Disruptive Behavior Disorders Child and Adolescent Screening and Rating Scales for Children, Adolescents, Parents and Teachers. West Bloomfield, Michigan: Integrative Therapy Institute Publication; 1994.
• 31. Bercik P, Collins SM, Verdu EF. Microbes and the gut-brain axis. Neurogastroenterol Motil. 2012;24(5):405-413.
• 32. Gkougka D, Mitropoulos K, Tzanakaki G, Panagouli E, Psaltopoulou T, Thomaidis L, et al. Gut microbiome and attention-deficit/hyperactivity disorder: A systematic review. Pediatr Res. 2022;92(6):1507-1519.
• 33. Boonchooduang N, Louthrenoo O, Chattipakorn N, Chattipakorn SC. Possible links between gut–microbiota and attention-deficit/hyperactivity disorders in children and adolescents. Eur J Nutr. 2020;59(8):3391-3403.
• 34. Jiang HY, Zhou YY, Zhou GL, Li YC, Yuan J, Li XH, et al. Gut microbiota profiles in treatment-naïve children with attention deficit hyperactivity disorder. Behav Brain Res. 2018;347:408-413.
• 35. Xu R, Wang Q. Towards understanding brain-gut-microbiome connections in Alzheimer's disease. BMC Syst Biol. 2016;10(Suppl 3):277-285.
• 36. Vogt NM, Romano KA, Darst BF, Engelman CD, Johnson SC, Carlsson CM, et al. The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer’s disease. Alzheimers Res Ther. 2018;10(1):124.
• 37. Nguyen TT, Kosciolek T, Daly RE, Vázquez-Baeza Y, Swafford A, Knight R, et al. Gut microbiome in schizophrenia: Altered functional pathways related to immune modulation and atherosclerotic risk. Brain Behav Immun. 2021;91:245-256.
• 38. Becker S, Sharma MJ, Callahan BL. ADHD and neurodegenerative disease risk: A critical examination of the evidence. Front Aging Neurosci. 2022;13:826213.
• 39. Vázquez JC, Martin de la Torre O, López Palomé J, Redolar-Ripoll D. Effects of caffeine consumption on attention deficit hyperactivity disorder (ADHD) treatment: A systematic review of animal studies. Nutrients. 2022;14(4):739.
• 40. Tripp G, Wickens JR. Neurobiology of ADHD. Neuropharmacology. 2009;57(7-8):579-589.
• 41. Hahn M, Lindemann V, Behrens M, Mulac D, Langer K, Esselen M, et al. Permeability of dopamine D2 receptor agonist hordenine across the intestinal and blood-brain barrier in vitro. PLoS One. 2022;17(6):e0269486.
• 42. Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011;472(7341):57-63.