Dikkat Eksikliği Hiperaktivite Bozukluğu olan Çocuklarda Serum Zonulin Düzeyleri ve Sosyal Biliş

Amaç: Son çalışmalarda dikkat eksikliği hiperaktivite bozukluğu (DEHB) tanılı hastaların bağırsak-beyin eksenindeki değişiklikler belirtilmiştir. Bu çalışmanın amacı, hem bağırsak-kan hem de kan-beyin bariyerlerinde geçirgenliği düzenlemek için bir modülatör olarak kabul edilen zonulinin serum düzeyinin DEHB tanılı çocuklarda DEHB belirtileriyle ilişkili olup olmadığını belirlemek ve zonulin ile sosyal biliş arasında bir ilişki olup olmadığını değerlendirmektir. Gereç ve Yöntemler: Zonulinin serum düzeyi, tedavi görmemiş 40 DEHB tanılı çocukta ve kontrol grubu olarak yaş ve cinsiyet yönünden eşleştirilmiş 40 sağlıklı çocukta enzime bağlı immünosorbent testi (enzyme-linked immunosorbent assay, ELISA) kullanılarak analiz edilmiştir. DEHB belirtileri, DuPaul DEHB Derecelendirme Ölçeği ile puanlanmış ve sosyal bilişsel becerileri incelemek için ise klinisyen tarafından gözlerden zihin okuma testi (reading the mind in the eyes test, RMET) uygulanmıştır. Bulgular: DEHB grubunda serum zonulin düzeyleri kontrol grubuna göre anlamlı olarak yüksek olarak bulunmuştur (p=0.010). Ayrıca, DEHB tanılı çocukların RMET puanları önemli ölçüde düşük bulunmuştur (p=0.007). Ek olarak, DEHB grubunda serum zonulin düzeyleri ile DEHB semptomları arasında istatistiksel olarak anlamlı pozitif korelasyon (p

Anahtar Kelimeler:

dikkat eksikliği hiperaktivite bozukluğu, zonulin, sosyal biliş, bağırsak-beyin ekseni

Serum Zonulin Levels and Social Cognition in Children with Attention Deficit Hyperactivity Disorder

Aim: Alterations in gut-brain axis of patients with attention deficit hyperactivity disorder (ADHD) have been indicated in recent studies. The aim of this study was to determine whether serum level of zonulin, considered to be a regulator of permeability in both gut-blood and blood-brain barriers, was associated with ADHD symptoms, and to evaluate the relationship between zonulin and social cognition in children with ADHD. Material and Methods: Serum level of zonulin was analyzed by enzyme-linked immunosorbent assay (ELISA) in 40 treatment-naive children with ADHD, and age and gender matched 40 healthy children as control group. DuPaul ADHD Rating Scale was used for ADHD symptoms and reading the mind in the eyes test (RMET) was administered by the clinician to examine the social cognitive abilities. Results: We found that serum zonulin levels were significantly higher in ADHD group compared to control group (p=0.010). Also, children with ADHD have significantly lower RMET scores (p=0.007). Furthermore, we found statistically significant positive correlations between serum zonulin levels and ADHD symptoms (p

Keywords:

attention deficit hyperactivity disorder, zonulin, social cognition, gut-brain axis,

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Polanczyk GV, Salum GA, Sugaya LS, Caye A, Rohde LA. Annual research review: A meta-analysis of the worldwide prevalence of mental disorders in children and adolescents. J Child Psychol Psychiatry. 2015;56(3):345-65.
Wittchen HU, Jacobi F, Rehm J, Gustavsson A, Svensson M, Jönsson B, et al. The size and burden of mental disorders and other disorders of the brain in Europe 2010. Eur Neuropsychopharmacol. 2011;21(9):655-79.
Willcutt EG. The prevalence of DSM-IV attention-deficit/hyperactivity disorder: a meta-analytic review. Neurotherapeutics. 2012;9(3):490-9.
American Psychiatric Association (APA). Diagnostic and statistical manual of mental disorders (DSM-5). 5th ed. Washington DC: American Psychiatric Association Publishing; 2013.
Uekermann J, Daum I. Social cognition in alcoholism: a link to prefrontal cortex dysfunction? Addiction. 2008;103(5):726-35.
Uekermann J, Kraemer M, Abdel-Hamid M, Schimmelmann BG, Hebebrand J, Daum I, et al. Social cognition in attention-deficit hyperactivity disorder (ADHD). Neurosci Biobehav Rev. 2010;34(5):734-43.
Bora E, Pantelis C. Meta-analysis of social cognition in attention-deficit/hyperactivity disorder (ADHD): comparison with healthy controls and autistic spectrum disorder. Psychol Med. 2016;46(4):699-716.
Özbaran B, Kalyoncu T, Köse S. Theory of mind and emotion regulation difficulties in children with ADHD. Psychiatry Res. 2018;270:117-22.
Şahin B, Karabekiroğlu K, Bozkurt A, Usta MB, Aydın M, Çobanoğlu C. The relationship of clinical symptoms with social cognition in children diagnosed with attention deficit hyperactivity disorder, specific learning disorder or autism spectrum disorder. Psychiatry Investig. 2018;15(12):1144-53.
Finegold SM. State of the art; microbiology in health and disease. Intestinal bacterial ﬂora in autism. Anaerobe. 2011;17(6): 367-8.
de Theije CG, Wu J, da Silva SL, Kamphuis PJ, Garssen J, Korte SM, et al. Pathways underlying the gut-to-brain connection in autism spectrum disorders as future targets for disease management. Eur J Pharmacol 2011;668(Suppl 1):s70-80.
Cenit MC, Nuevo IC, Codoñer-Franch P, Dinan TG, Sanz Y. Gut microbiota and attention deficit hyperactivity disorder: new perspectives for a challenging condition. Eur Child Adolesc Psychiatry. 2017;26(9):1081-92.
Dam SA, Mostert JC, Szopinska-Tokov JW, Bloemendaal M, Amato M, Arias-Vasquez A. The role of the gut-brain axis in attention-deficit/hyperactivity disorder. Gastroenterol Clin North Am. 2019;48(3):407-31.
Liu L, Zhu G. Gut-brain axis and mood disorder. Front Psychiatry. 2018;9:223.
Fasano A. Regulation of intercellular tight junctions by zonula occludens toxin and its eukaryotic analogue zonulin. Ann N Y Acad Sci. 2000;915:214-22.
Fasano A. Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiol Rev. 2011;91(1):151-75.
El Asmar R, Panigrahi P, Bamford P, Berti I, Not T, Coppa GV, et al. Host-dependent zonulin secretion causes the impairment of the small intestine barrier function after bacterial exposure. Gastroenterology. 2002;123(5):1607-15.
Fasano A. Zonulin, regulation of tight junctions, and autoimmune diseases. Ann N Y Acad Sci. 2012;1258(1):25-33.
Asbjornsdottir B, Snorradottir H, Andresdottir E, Fasano A, Lauth B, Gudmundsson LS, et al. Zonulin-dependent intestinal permeability in children diagnosed with mental disorders: A systematic review and meta-analysis. Nutrients. 2020;12(7):1982.
Esnafoglu E, Cırrık S, Ayyıldız SN, Erdil A, Yurdakul Ertürk EY, Daglı A, et al. Increased serum zonulin levels as an intestinal permeability marker in autistic subjects. J Pediatr. 2017;188:240-4.
Özyurt G, Öztürk Y, Appak YÇ, Arslan FD, Baran M, Karakoyun İ, et al. Increased zonulin is associated with hyperactivity and social dysfunctions in children with attention deficit hyperactivity disorder. Compr Psychiatry. 2018;87:138-42.
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):980-8.
Gökler B, Ünal F, Pehlivantürk B, Çengel Kültür E, 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):109-16.
Ünal F, Öktem F, Çetin Çuhadaroğlu F, Çengel Kültür SE, Akdemir D, Foto Özdemir D, et al. Reliability and validity of the schedule for affective disorders and schizophrenia for school-age children-present and lifetime version, DSM-5 November 2016-Turkish adaptation (K-SADS-PL-DSM-5-T). Turk Psikiyatri Derg. 2019;30(1):42-50.
DuPaul GJ, Power TJ, Anastopoulos AD, Reid R. ADHD rating scale IV: checklists, norms and clinical interpretation. New York: Guilford Press; 1998.
Yurteri N, Şahin İE, Tufan AE. Altered serum levels of vascular endothelial growth factor and glial-derived neurotrophic factor but not fibroblast growth factor-2 in treatment-naive children with attention deficit/hyperactivity disorder. Nord J Psychiatry. 2019;73(4-5):302-7.
Akay AP, Resmi H, Güney SA, Erkuran HÖ, Özyurt G, Sargin E, et al. Serum brain-derived neurotrophic factor levels in treatment-naive boys with attention-deficit/hyperactivity disorder treated with methylphenidate: an 8-week, observational pretest-posttest study. Eur Child Adolesc Psychiatry. 2018;27(1):127-35.
Yurteri N, Şahin İE. Decreased serum levels of total and high molecular weight adiponectin in treatment-naive children with ADHD. Anadolu Psikiyatri Derg. 2020;21(6):633-40.
Baron-Cohen S, Jolliffe T, Mortimore C, Robertson M. Another advanced test of theory of mind: evidence from very high functioning adults with autism or asperger syndrome. J Child Psychol Psychiatry. 1997;38(7):813-22.
Baron-Cohen S, Wheelwright S, Hill J, Raste Y, Plumb I. The "reading the mind in the eyes" test revised version: a study with normal adults, and adults with Asperger syndrome or high-functioning autism. J Child Psychol Psychiatry. 2001;42(2):241-51.
Girli A. Psychometric properties of the Turkish child and adult form of “reading the mind in the eyes test”. Psychology. 2014;5(11):1321-37.
Aydoğan Avşar P, Işık Ü, Aktepe E, Kılıç F, Doğuç DK, Büyükbayram Hİ. Serum zonulin and claudin-5 levels in children with attention-deficit/hyperactivity disorder. Int J Psychiatry Clin Pract. 2020;[Epub ahead of print]. doi: 10.1080/13651501.2020.1801754.
Küme T, Acar S, Tuhan H, Çatlı G, Anık A, Gürsoy Çalan Ö, et al. The relationship between serum zonulin level and clinical and laboratory parameters of childhood obesity. J Clin Res Pediatr Endocrinol. 2017;9(1):31-8.
Moreno-Navarrete JM, Sabater M, Ortega F, Ricart W, Fernández-Real JM. Circulating zonulin, a marker of intestinal permeability, is increased in association with obesity-associated insulin resistance. PLoS One. 2012;7(5):e37160.
Brock M, Trenkmann M, Gay RE, Gay S, Speich R, Huber LC. MicroRNA-18a enhances the interleukin-6-mediated production of the acute-phase proteins fibrinogen and haptoglobin in human hepatocytes. J Biol Chem 2011;286(46):40142-50.
Emanuele E, Orsi P, Boso M, Broglia D, Brondino N, Barale F, et al. Low-grade endotoxemia in patients with severe autism. Neurosci Lett. 2010;471(3):162-5.
Cortese S, Angriman M, Comencini E, Vincenzi B, Maffeis C. Association between inflammatory cytokines and ADHD symptoms in children and adolescents with obesity: A pilot study. Psychiatry Res 2019;278:7-11.
Welch MG, Margolis KG, Li Z, Gershon MD. Oxytocin regulates gastrointestinal motility, inflammation, macromolecular permeability, and mucosal maintenance in mice. Am J Physiol Gastrointest Liver Physiol. 2014;307(8):G848-62.
Taurines R, Schwenck C, Lyttwin B, Schecklmann M, Jans T, Reefschläger L, et al. Oxytocin plasma concentrations in children and adolescents with autism spectrum disorder: correlation with autistic symptomatology. Atten Defic Hyperact Disord. 2014;6(3):231-9.
Demirci E, Ozmen S, Kilic E, Oztop DB. The relationship between aggression, empathy skills and serum oxytocin levels in male children and adolescents with attention deficit and hyperactivity disorder. Behav Pharmacol. 2016;27(8):681-8.
Fasano A, Not T, Wang W, Uzzau S, Berti I, Tommasini A, et al. Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease. Lancet. 2000;355(9214):1518-9.
Zak-Gołąb A, Kocełak P, Aptekorz M, Zientara M, Juszczyk L, Martirosian G, et al. Gut microbiota, microinflammation, metabolic profile, and zonulin concentration in obese and normal weight subjects. Int J Endocrinol. 2013;2013:674106.
Zhang D, Zhang L, Zheng Y, Yue F, Russell RD, Zeng Y. Circulating zonulin levels in newly diagnosed Chinese type 2 diabetes patients. Diabetes Res Clin Pract. 2014;106(2):312-8.
Jayashree B, Bibin YS, Prabhu D, Shanthirani CS, Gokulakrishnan K, Lakshmi BS, et al. Increased circulatory levels of lipopolysaccharide (LPS) and zonulin signify novel biomarkers of proinﬂammation in patients with type 2 diabetes. Mol Cell Biochem. 2014;388(1-2):203-10.
Sapone A, de Magistris L, Pietzak M, Clemente MG, Tripathi A, Cucca F, et al. Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives. Diabetes. 2006;55(5):1443-9.
Fasano A. Intestinal permeability and its regulation by zonulin: diagnostic and therapeutic implications. Clin Gastroenterol Hepatol. 2012;10(10):1096-100.
Sturgeon C, Fasano A. Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inﬂammatory diseases. Tissue Barriers. 2016;4(4):e1251384.
Stevens BR, Goel R, Seungbum K, Richards EM, Holbert RC, Pepine CJ, et al. Increased human intestinal barrier permeability plasma biomarkers zonulin and FABP2 correlated with plasma LPS and altered gut microbiome in anxiety or depression. Gut. 2018;67(8):1555-7.
Linninge C, Jönsson P, Bolinsson H, Önning G, Eriksson J, Johansson G, et al. Effects of acute stress provocation on cortisol levels, zonulin and inflammatory markers in low- and high-stressed men. Biol Psychol. 2018;138:48-55.
Mörkl S, Lackner S, Meinitzer A, Mangge H, Lehofer M, Halwachs B, et al. Gut microbiota, dietary intakes and intestinal permeability reflected by serum zonulin in women. Eur J Nutr. 2018;57(8):2985-97.
Raftery T, Martineau AR, Greiller CL, Ghosh S, McNamara D, Bennett K, et al. Effects of vitamin D supplementation on intestinal permeability, cathelicidin and disease markers in Crohn's disease: Results from a randomised double-blind placebo-controlled study. United European Gastroenterol J. 2015;3(3):294-302.
Souza NC, Mendonca JN, Portari GV, Jordao Junior AA, Marchini JS, Chiarello PG. Intestinal permeability and nutritional status in developmental disorders. Altern Ther Health Med. 2012;18(2):19-24.