Otizm Spektrum Bozukluğunun Moleküler Yönleri: İmmün Sistem ve Mikrobiyom Üzerine Bulgular

Görülme sıklığı artmakta olan otizm spektrum bozuklukları, sosyal gelişimde yetersizlik, tekrarlayıcı motor hareketler ve dil ve konuşma güçlükleri gibi heterojen nörogelişimsel bozukluklar ile karakterize bir tanı gurubu için kullanılan şemsiye bir terimdir. Otizmin, farklı kromozomal bölgelerde ortaya çıkabilen mutasyonlarla ilişkili olabileceği, dolayısıyla hastalığın etiyolojisinde genetik etmenlerin etkili olabileceği öne sürülmüştür. Bağışıklık sisteminde meydana gelebilecek değişimler ve immünogenetik, hastalığın etiyolojisine katkısı olduğu ileri sürülen diğer etmenlerdir. Otizmin ortaya çıkışında genetik etkenlerin yanında çevresel etkenlerin sebep olabileceği fonksiyonel bozukluklar da göz ardı edilmemelidir. Bu anlamda, bağırsak mikrobiyomunun otizm ile ilişkili olabileceği güncel çalışmalarla bildirilmiş olup, bozulmuş mikrobiyomun, bağışıklık sistemi ve merkezi sinir sistemini etkileyerek otistik davranışlara sebep olabileceği önerilmiştir. Bu çalışmada, otizmin etiyolojisini kavramak üzere yapılmış güncel çalışmalar derlenmiş olup, otizm tedavisinde gen ve mikrobiyom odaklı tedavi seçeneklerinin potansiyelleri tartışılmıştır.

Molecular Aspects of Autism Spectrum Disorder: The Findings on theImmune System and Microbiome

As one of the increasing problems of our age, autism spectrum disorder is an umbrella term used for heterogeneous neurodevelopmental disorders such as inadequacy in social development, repetitive motor movements, and retardation in language development. Autism has been argued to be associated with mutations that may occur in different chromosomal regions. Therefore, it has been suggested that genetic factors may play a role in the etiology of the disease. Immunological and immunogenetic changes are the other factors that have been suggested to contribute to the etiology of the disease. In the emergence of autism, besides the genetic factors, the potential effects of environmental factors on functional disorders should not be ignored. In this sense, it has been reported that the intestinal microbiome may be involved in the etiology and/or pathophysiology of autism, and it has been shown that impaired microbiome can cause autistic behaviors by affecting the immune system and central nervous system. In this work, current studies to comprehend the etiology of autism have been reviewed and the potentials of gene and microbiome-oriented therapeutic options in the treatment of autism have been discussed.

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Baron-Cohen S. Leo Kanner, Hans Asperger, and the discovery of autism. Lancet. 2015;386:1329-1330.
Yates K, Le Couteur A. Diagnosing autism/autism spectrum disorders. Paediatr Child Heal (United Kingdom). 2016;26:513-518.
Baio J, Wiggins L, Christensen DL, et al. Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2014. MMWR Surveill Summ. 2018.
Wimberley T, Agerbo E, Pedersen CB, et al. Otitis media, antibiotics, and risk of autism spectrum disorder. Autism Res. 2018;11:1432-1440.
Petinou K, Minaidou D. Neurobiological Bases of Autism Spectrum Disorders and Implications for Early Intervention: A Brief Overview. Folia Phoniatr Logop. 2017;69:38-42.
Sadybekov A, Tian C, Arnesano C, Katritch V, Herring BE. An autism spectrum disorder-related de novo mutation hotspot discovered in the GEF1 domain of Trio. Nat Commun. 2017;8:1-13.
Eapen V, Nicholls L, Spagnol V, Mathew NE. Current status of biological treatment options in Autism Spectrum Disorder. Asian J Psychiatr. 2017;30:1-10.
Jeste SS, Geschwind DH. Disentangling the heterogeneity of autism spectrum disorder through genetic findings. Nat Rev Neurol. 2014;10:74-81.
Fett-Conte AC, Bossolani-Martinis AL, Pereira-Nascimento P. Genetic Etiology of Autism. In: Fitzgerald M, ed. Recent Advances in Autism Spectrum Disorders. Vol. I. Rijeka, Croatia: IntechOpen; 2013:216-248.
Mosca E, Bersanelli M, Gnocchi M et al. Network Diffusion-Based Prioritization of Autism Risk Genes Identifies Significantly Connected Gene Modules. Front Genet. 2017;8:1-14
Vincent JB, Herbrick J-A, Gurling HMD, Bolton PF, Roberts W, Scherer SW. Identification of a Novel Gene on Chromosome 7q31 That Is Interrupted by a Translocation Breakpoint in an Autistic Individual. Am J Hum Genet. 2000;67:510–514.
Petek E, Windpassinger C, Vincent JB et al. Disruption of a Novel Gene (IMMP2L) by a Breakpoint in 7q31 Associated with Tourette Syndrome. Am J Hum Genet. 2001;68:848-858.
Muhle R, Rentacoste S, Rapin I. The genetics of autism. Pediatrics. 2004;113:472-486.
Vatsa N, Jana NR. UBE3A and Its Link With Autism. Front Mol Neurosci. 2018;11:448.
Lammert DB, Howell BW. RELN Mutations in Autism Spectrum Disorder. Front Cell Neurosci. 2016;10:1-9.
Phelan K, McDermid HE. The 22q13.3 deletion syndrome (Phelan-McDermid syndrome). Mol Syndromol. 2012;2:186-201.
Abrahams BS, Geschwind DH. Advances in autism genetics: On the threshold of a new neurobiology. Nat Rev Genet. 2008;9:341-355.
Yosunkaya E. Otizm Etyolojisinde Genetik ve Güncel Perspektif. İstanbul Tıp Fakültesi Derg. 2013;76:84-88.
Earl RK, Turner TN, Mefford HC, et al. Clinical phenotype of ASD-associated DYRK1A haploinsufficiency. Mol Autism. 2017;8:1-15.
Onay H, Kacamak D, Kavasoglu AN et al. Mutation analysis of the NRXN1 gene in autism spectrum disorders. Balk J Med Genet. 2016;19:17-22.
Etherton M, Foldy C, Sharma M et al. Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function. Proc Natl Acad Sci. 2011;108:13764-13769.
Moessner R, Marshall CR, Sutcliffe JS et al. Contribution of SHANK3 Mutations to Autism Spectrum Disorder. Am J Hum Genet. 2007;81:1289-1297.
Jones R, Cadby G, Blangero J, Abraham L, Whitehouse A, Moses E. MACROD2 gene associated with autistic-like traits in a general population sample. Psychiatr Genet. 2014;24:241-248.
Samaco RC, Hogart A, LaSalle JM. Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3. Hum Mol Genet. 2005;14:483-492.
Watson P. Angelman syndrome phenotype associated with mutations in MECP2, a gene encoding a methyl CpG binding protein. J Med Genet. 2001;38:224-228.
Carney RM, Wolpert CM, Ravan SA et al. Identification of MeCP2 mutations in a series of females with autistic disorder. Pediatr Neurol. 2003;28:205-211.
Rutter M. Aetiology of autism: Findings and questions. J Intellect Disabil Res. 2005;49:231-238.
Harris SW, Hessl D, Goodlin-Jones B et al. Autism Profiles of Males With Fragile X Syndrome. Am J Ment Retard. 2008;113:427-438.
Shiina T, Inoko H, Kulski JK. An update of the HLA genomic region, locus information and disease associations: 2004. Tissue Antigens. 2004;64:631-649.
Torres AR, Sweeten TL, Johnson RC et al. Common genetic variants found in HLA and KIR immune genes in autism spectrum disorder. Front Neurosci. 2016;10:1-13.
Tilburgs T, Evans JH, Crespo ÂC, Strominger JL. The HLA-G cycle provides for both NK tolerance and immunity at the maternal–fetal interface. Proc Natl Acad Sci. 2015;112:13312-13317.
Guerini FR, Bolognesi E, Chiappedi M et al. An HLA-G∗14bp insertion/deletion polymorphism associates with the development of autistic spectrum disorders. Brain Behav Immun. 2015;44:207-212.
Chien YL, Wu YY, Chen CH et al. Association of HLA-DRB1 alleles and neuropsychological function in autism. Psychiatr Genet. 2012;22:46-49.
Choi GB, Yim YS, Wong H et al. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science. 2016;351:933-939.
Odell D, Maciulis A, Cutler A et al. Confirmation of the association of the C4B null allelle in autism. Hum Immunol. 2005;66:140-145.
Mostafa GA, Shehab AA. The link of C4B null allele to autism and to a family history of autoimmunity in Egyptian autistic children. J Neuroimmunol. 2010;223:115-119.
Warren RP, Burger RA, Odell D, Torres AR, Warren WL. Decreased Plasma Concentrations of the C4B Complement Protein in Autism. Arch Pediatr Adolesc Med. 1994;148:180-183.
Meltzer A, Van De Water J. The Role of the Immune System in Autism Spectrum Disorder. Neuropsychopharmacology. 2017;42:284-298.
Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005;57:67-81.
Pardo CA, Vargas DL, Zimmerman AW. Immunity, neuroglia and neuroinflammation in autism. Int Rev Psychiatry. 2005;17:485-495.
Masi A, Glozier N, Dale R, Guastella AJ. The Immune System, Cytokines, and Biomarkers in Autism Spectrum Disorder. Neurosci Bull. 2017;33:194-204.
Croonenberghs J, Wauters A, Devreese K et al. Increased serum albumin, gamma globulin, immunoglobulin IgG, and IgG2 and IgG4 in autism. Psychol Med. 2002;32:1457-1463.
Wei H, Zou H, Sheikh AM et al. IL-6 is increased in the cerebellum of autistic brain and alters neural cell adhesion, migration and synaptic formation. J Neuroinflammation. 2011;8:52.
Castellani ML, Conti CM, Kempuraj DJ et al. Autism and immunity: Revisited study. Int J Immunopathol Pharmacol. 2009;22:15-19.
Jyonouchi H, Sun S, Le H. Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression. J Neuroimmunol. 2001;120:170-179.
Jones KL, Croen LA, Yoshida CK et al. Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation. Mol Psychiatry. 2017;22:273-279.
Dipasquale V, Cutrupi MC, Colavita L, Manti S, Cuppari C, Salpietro C. Neuroinflammation in Autism Spectrum Disorders: Role of High Mobility Group Box 1 Protein. Int J Mol Cell Med. 2017;6:148–155.
Onore C, Careaga M, Ashwood P. The role of immune dysfunction in the pathophysiology of autism. Brain Behav Immun. 2012;26:383-392.
Smith DA, Germolec DR. Introduction to immunology and autoimmunity. Environ Health Perspect. 1999;107:661–665.
Edmiston E, Ashwood P, Van de Water J. Autoimmunity, Autoantibodies, and Autism Spectrum Disorder. Biol Psychiatry. 2017;81:383-390.
Nadeem A, Ahmad SF, Bakheet SA et al. Toll-like receptor 4 signaling is associated with upregulated NADPH oxidase expression in peripheral T cells of children with autism. Brain Behav Immun. 2017;61:146-154.
Bedard K, Krause K-H. The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology. Physiol Rev. 2007;87:245-313.
Yu B, Meng F, Yang Y, Liu D, Shi K. NOX2 antisense attenuates hypoxia-induced oxidative stress and apoptosis in cardiomyocyte. Int J Med Sci. 2016;13:646–652.
Sorce S, Stocker R, Seredenina T et al. NADPH oxidases as drug targets and biomarkers in neurodegenerative diseases: What is the evidence? Free Radic Biol Med. 2017;112:387-396.
Lucas K, Maes M. Role of the toll like receptor (TLR) radical cycle in chronic inflammation: Possible treatments targeting the TLR4 pathway. Mol Neurobiol. 2013;48:190-204.
Enstrom AM, Onore CE, Van de Water JA, Ashwood P. Differential monocyte responses to TLR ligands in children with autism spectrum disorders. Brain Behav Immun. 2010;24:64-71.
Le Belle JE, Sperry J, Ngo A et al. Maternal inflammation contributes to brain overgrowth and autism-associated behaviors through altered redox signaling in stem and progenitor cells. Stem Cell Reports. 2014;3:725–734.
Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah I, Van de Water J. Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain Behav Immun. 2011;25:40-45.
Gadient RA, Patterson PH. Leukemia inhibitory factor, interleukin 6, and other cytokines using the GP130 transducing receptor: Roles in inflammation and injury. Stem Cells. 1999;17:127-137.
Garbett K, Ebert PJ, Mitchell A et al. Immune transcriptome alterations in the temporal cortex of subjects with autism. Neurobiol Dis. 2008;30:303-311.
Siniscalco D, Schultz S, Brigida AL, Antonucci N. Inflammation and neuro-immune dysregulations in autism spectrum disorders. Pharmaceuticals. 2018;11:1-14.
Onore C, Enstrom A, Krakowiak P et al. Decreased cellular IL-23 but not IL-17 production in children with autism spectrum disorders. J Neuroimmunol. 2009;216:126-129.
Ashwood P, Enstrom A, Krakowiak P et al. Decreased transforming growth factor beta1 in autism: A potential link between immune dysregulation and impairment in clinical behavioral outcomes. J Neuroimmunol. 2008;204:149-153.
Gupta S, Aggarwal S, Heads C. Dysregulated immune system in children with autism - Beneficial effects of intravenous immune globulin on autistic characteristics. J Autism Dev Disord. 1996;26:439-452.
Gupta S. Immunological treatments for autism. J Autism Dev Disord. 2000;30:475-479.
Yates A. Autism: the case for left hemispheric damage. Ariz Med. 1984;41:395-397.
Rojas DC, Bawn SD, Benkers TL, Reite ML, Rogers SJ. Smaller left hemisphere planum temporale in adults with autistic disorder. Neurosci Lett. 2002;328:237-240.
Theoharides TC, Alysandratos KD, Angelidou A et al. Mast cells and inflammation. Biochim Biophys Acta - Mol Basis Dis. 2012;1822:21-33.
Benger M, Kinali M, Mazarakis ND. Autism spectrum disorder: Prospects for treatment using gene therapy. Mol Autism. 2018;9:1-10.
Mendell JR, Zaidy S Al, Shell R et al. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. N Engl J Med. 2017;377:1713–1722.
Matagne V, Ehinger Y, Saidi L et al. A codon-optimized Mecp2 transgene corrects breathing deficits and improves survival in a mouse model of Rett syndrome. Neurobiol Dis. 2017;99:1-11.
Tillotson R, Selfridge J, Koerner M V. et al. Radically truncated MeCP2 rescues Rett syndrome-like neurological defects. Nature. 2017;550:398-401.
Robinson L, Guy J, McKay L et al. Morphological and functional reversal of phenotypes in a mouse model of Rett syndrome. Brain. 2012;135:2699–2710.
Gadalla KKE, Vudhironarit T, Hector RD et al. Development of a Novel AAV Gene Therapy Cassette with Improved Safety Features and Efficacy in a Mouse Model of Rett Syndrome. Mol Ther Methods Clin Dev. 2017;5:180-190.
Kole R, Krainer AR, Altman S. RNA therapeutics: Beyond RNA interference and antisense oligonucleotides. Nat Rev Drug Discov. 2012;11:125-140.
Sztainberg Y, Chen HM, Swann JW et al. Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides. Nature. 2015;528:123-126.
Meng L, Ward AJ, Chun S, Bennett CF, Beaudet AL, Rigo F. Towards a therapy for Angelman syndrome by targeting a long non-coding RNA. Nature. 2015;518:409-412.
Wang Y, Kasper LH. The role of microbiome in central nervous system disorders. Brain Behav Immun. 2014;38:1-12.
Carabotti M, Scirocco A, Antonietta M, Severi C. The gut-brain axis : interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol. 2015;28:203–209.
Yang Y, Tian J, Yang B. Targeting gut microbiome: A novel and potential therapy for autism. Life Sci. 2018;194:111-119.
Nithianantharajah J, Balasuriya GK, Franks AE, Hill-Yardin EL. Using Animal Models to Study the Role of the Gut–Brain Axis in Autism. Curr Dev Disord Reports. 2017;4:28-36.
Grubišić V, Parpura V. The second brain in autism spectrum disorder: could connexin 43 expressed in enteric glial cells play a role? Front Cell Neurosci. 2015;9:1-5.
Zhu X, Han Y, Du J, Liu R, Jin K, Yi W. Microbiota-gut-brain axis and the central nervous system. Oncotarget. 2017;8:53829–53838.
Wu WL. Association Among Gut Microbes, Intestinal Physiology, and Autism. EBioMedicine. 2017;25:11–12.
Kudret Adiloğlu A, Kudret Adiloğlu D. The Interaction of Diet, Microbiota, and Antimicrobial Peptides in the Gastrointestinal Ecosystem. Niche. 2014;3:28-32.
Furness JB. The enteric nervous system and neurogastroenterology. Nat Rev Gastroenterol Hepatol. 2012;9:286-294.
Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012;13:701-712.
Ho P, Ross DA. More Than a Gut Feeling: The Implications of the Gut Microbiota in Psychiatry. Biol Psychiatry. 2017;81:e35-37.
Macpherson AJ, Harris NL. Interactions between commensal intestinal bacteria and the immune system. Nat Rev Immunol. 2004;4:478-485.
Horvath K, Perman JA. Autistic disorder and gastrointestinal disease. Curr Opin Pediatr. 2002;14:583-587.
Hsiao EY. Gastrointestinal issues in autism spectrum disorder. Harv Rev Psychiatry. 2014;22:104-111.
Cao X, Lin P, Jiang P, Li C. Characteristics of the gastrointestinal microbiome in children with autism spectrum disorder: a systematic review. Shanghai Arch psychiatry. 2013;25:342-353.
Molloy CA, Manning-Courtney P. Prevalence of chronic gastrointestinal symptoms in children with autism and autistic spectrum disorders. Autism. 2003;7:165-171.
Jolanta Wasilewska J, Klukowski M. Gastrointestinal symptoms and autism spectrum disorder: links and risks-a possible new overlap syndrome. Pediatr Heal Med Ther. 2015;6:153–166.
Nikolov RN, Bearss KE, Lettinga J et al. Gastrointestinal symptoms in a sample of children with pervasive developmental disorders. J Autism Dev Disord. 2009;39:405-413.
Parracho HMRT, Bingham MO, Gibson GR, McCartney AL. Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. J Med Microbiol. 2005;54:987-991.
Meyza KZ, Defensor EB, Jensen AL et al. The BTBR T(+)tf/J mouse model for autism spectrum disorders-in search of biomarkers. Behav Brain Res. 2013;251:25-34.
Golubeva A V., Joyce SA, Moloney G et al. Microbiota-related Changes in Bile Acid & Tryptophan Metabolism are Associated with Gastrointestinal Dysfunction in a Mouse Model of Autism. EBioMedicine. 2017;24:166-178.
Malkova N V., Yu CZ, Hsiao EY, Moore MJ, Patterson PH. Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain Behav Immun. 2012;26:607-616.
Hsiao EY, McBride SW, Hsien S et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell. 2013;155:1451-1463.
Krajmalnik-Brown R, Lozupone C, Kang D-W, Adams JB. Gut bacteria in children with autism spectrum disorders: challenges and promise of studying how a complex community influences a complex disease. Microb Ecol Heal Dis. 2015;26:26914.
Guhathakurta S, Ghosh S, Sinha S et al. Serotonin transporter promoter variants: Analysis in Indian autistic and control population. Brain Res. 2006;1092:28-35.
Muller CL, Anacker AMJ, Veenstra-VanderWeele J. The serotonin system in autism spectrum disorder: From biomarker to animal models. Neuroscience. 2016;321:24-41.
Sodhi MSK, Sanders-Bush E. Serotonin and brain development. Int Rev Neurobiol. 2004;59:111-174.
Rex A, Fink H. Neurotransmitter and Behaviour : Serotonin and Anxiety. Psychiatr Disord Trends Dev. 2007;19:468-470.
Slattery JA, Page AJ, Dorian CL, Brierley SM, Blackshaw LA. Potentiation of mouse vagal afferent mechanosensitivity by ionotropic and metabotropic glutamate receptors. J Physiol. 2006;577:295-306.
Thibault K, Van Steenwinckel J, Brisorgueil MJ et al. Serotonin 5-HT2A receptor involvement and Fos expression at the spinal level in vincristine-induced neuropathy in the rat. Pain. 2008;140:305-322.
Warren RP, Margaretten NC, Pace NC, Foster A. Immune abnormalities in patients with autism. J Autism Dev Disord. 1986;16:189-197.
Whyte A, Jessen T, Varney S, Carneiro AMD. Serotonin transporter and integrin beta 3 genes interact to modulate serotonin uptake in mouse brain. Neurochem Int. 2014;73:122-126.
Tordjman S, Gutknecht L, Carlier M et al. Role of the serotonin transporter gene in the behavioral expression of autism. Mol Psychiatry. 2001;6:434-439.
Şener EF, Korkmaz K, Öztop DB, Zararsız G, Özkul Y. Investigation of SLC6A4 gene expression in autism spectrum disorders. J Clin Exp Investig. 2015;6:165-169.
Huang CH, Santangelo SL. Autism and serotonin transporter gene polymorphisms: A systematic review and meta-analysis. Am J Med Genet Part B Neuropsychiatr Genet. 2008;147B:903-913.
Bernier R, Golzio C, Xiong B et al. Disruptive CHD8 mutations define a subtype of autism early in development. Cell. 2014;158:263-276.
Margolis KG, Li Z, Stevanovic K, et al. Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function. J Clin Invest. 2016;126:2221-2235.
Heredia DJ, Gershon MD, Koh SD, Corrigan RD, Okamoto T, Smith TK. Important role of mucosal serotonin in colonic propulsion and peristaltic reflexes: In vitro analyses in mice lacking tryptophan hydroxylase 1. J Physiol. 2013;591:5939-5957.
Mawe GM, Hoffman JM. Serotonin signalling in the gut-functions, dysfunctions and therapeutic targets. Nat Rev Gastroenterol Hepatol. 2013;10:473-486.
Newell C, Bomhof MR, Reimer RA, Hittel DS, Rho JM, Shearer J. Ketogenic diet modifies the gut microbiota in a murine model of autism spectrum disorder. Mol Autism. 2016;7:37.
Klein MS, Newell C, Bomhof MR, et al. Metabolomic Modeling to Monitor Host Responsiveness to Gut Microbiota Manipulation in the BTBRT+tf/jMouse. J Proteome Res. 2016;4:1143-1150.
Kennedy PJ, Cryan JF, Dinan TG, Clarke G. Kynurenine pathway metabolism and the microbiota-gut-brain axis. Neuropharmacology. 2017;112:399-412.
Lieu T, Jayaweera G, Bunnett NW. GPBA: A GPCR for bile acids and an emerging therapeutic target for disorders of digestion and sensation. Br J Pharmacol. 2014;171:1156-1166.
Alemi F, Poole DP, Chiu J et al. The receptor TGR5 mediates the prokinetic actions of intestinal bile acids and is required for normal defecation in mice. Gastroenterology. 2013;144:145-154.
Sayin SI, Wahlström A, Felin J et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 2013;17:225-235.
Inagaki T, Moschetta A, Lee Y-K et al. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci. 2006;103:3920-3925.
Joyce SA, MacSharry J, Casey PG et al. Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut. Proc Natl Acad Sci. 2014;111:7421-7426.
Williams PG, Sears LL, Allard A. Sleep problems in children with autism. J Sleep Res. 2004;13:265-268.
Rossignol, DA; Frye R. Melatonin in autism spectrum disorders: A systematic review and meta-analysis. Dev Med Child Neurol. 2011;53:783-792.
Melke J, Goubran Botros H, Chaste P et al. Abnormal melatonin synthesis in autism spectrum disorders. Mol Psychiatry. 2008;13:90-98.
Simonneaux V. Generation of the Melatonin Endocrine Message in Mammals: A Review of the Complex Regulation of Melatonin Synthesis by Norepinephrine, Peptides, and Other Pineal Transmitters. Pharmacol Rev. 2003;55:325-395.
Andersen IM, Kaczmarska JA, McGrew SG, Malow BA. Melatonin for insomnia in children with autism spectrum disorders. J Child Neurol. 2008;23:482-485.
Toma C, Rossi M, Sousa I et al. Is ASMT a susceptibility gene for autism spectrum disorders? A replication study in European populations. Mol Psychiatry. 2007;12:977-979.
Zerbo O, Qian Y, Yoshida C, Grether JK, Van de Water J, Croen LA. Maternal Infection During Pregnancy and Autism Spectrum Disorders. J Autism Dev Disord. 2015;45:4015-4025.
Lee BK, Magnusson C, Gardner RM et al. Maternal hospitalization with infection during pregnancy and risk of autism spectrum disorders. Brain, Behav Immun. 2015;44:100-105.
Ceylani T, Jakubowska-Doğru E, Gurbanov R, Teker HT, Gozen AG. The effects of repeated antibiotic administration to juvenile BALB/c mice on the microbiota status and animal behavior at the adult age. Heliyon. 2018;4:e00644.
Bolte ER. Autism and clostridium tetani. Med Hypotheses. 1998;51:133-144.
Niehus RCL. Early medical history of children with autism spectrum disorders. 2006;27:120-127.
Dethlefsen L, Relman DA. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. PNAS. 2011;108:4554-4561.
Sandler RH, Finegold SM, Bolte ER et al. Short-Term Benefit From Oral Vancomycin Treatment of Regressive-Onset Autism. J Child Neurol. 2000;15:429-435.
Shaw W. Biological Treatments for Autism and PDD. 3rd revise. (Shaw W, ed.). USA: Sunflower Pub; 2008.
Donaldson GP, Lee SM, Mazmanian SK. Gut biogeography of the bacterial microbiota. Nat Rev Microbiol. 2015;14:20-32.
Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol. 2009;9:313-323.
Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr. 1995;125:1401-1412.
Strati F, Cavalieri D, Albanese D et al. New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome. 2017;5:24.
De Angelis M, Piccolo M, Vannini L et al. Fecal Microbiota and Metabolome of Children with Autism and Pervasive Developmental Disorder Not Otherwise Specified. PLoS One. 2013;8:e76993.
Grimaldi R, Cela D, Swann JR et al. In vitro fermentation of B-GOS: Impact on faecal bacterial populations and metabolic activity in autistic and non-autistic children. FEMS Microbiol Ecol. 2016;93:fiw233.
Finegold SM, Molitoris D, Song Y et al. Gastrointestinal Microflora Studies in Late‐Onset Autism. Clin Infect Dis. 2002;35:S6-S16.
Kang DW, Park JG, Ilhan ZE et al. Reduced Incidence of Prevotella and Other Fermenters in Intestinal Microflora of Autistic Children. PLoS One. 2013;8:e68322.
Wang L, Christophersen CT, Sorich MJ, Gerber JP, Angley MT, Conlon MA. Increased abundance of Sutterella spp. and Ruminococcus torques in feces of children with autism spectrum disorder. Mol Autism. 2013;4:42.
Argou-Cardozo I, Zeidán-Chuliá F. Clostridium Bacteria and Autism Spectrum Conditions: A Systematic Review and Hypothetical Contribution of Environmental Glyphosate Levels. Med Sci. 2018;6:E29.
Finegold SM, Summanen PH, Downes J, Corbett K, Komoriya T. Detection of Clostridium perfringens toxin genes in the gut microbiota of autistic children. Anaerobe. 2017;45:133-137.
Neufeld KM, Kang N, Bienenstock J, Foster JA. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil. 2011;23:255-264.
Desbonnet L, Clarke G, Traplin A et al. Gut microbiota depletion from early adolescence in mice: Implications for brain and behaviour. Brain Behav Immun. 2015;48:165-173.
Kang DW, Adams JB, Gregory AC et al. Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: An open-label study. Microbiome. 2017;5:10.
Kang DW, Ilhan ZE, Isern NG et al. Differences in fecal microbial metabolites and microbiota of children with autism spectrum disorders. Anaerobe. 2018;49:121-131.
Tabouy L, Getselter D, Ziv O et al. Dysbiosis of microbiome and probiotic treatment in a genetic model of autism spectrum disorders. Brain Behav Immun. 2018;73:310-319.
Kałuzna-Czaplińska J, Błaszczyk S. The level of arabinitol in autistic children after probiotic therapy. Nutrition. 2012;28:124-126.
Grossi E, Melli S, Dunca D, Terruzzi V. Unexpected improvement in core autism spectrum disorder symptoms after long-term treatment with probiotics. SAGE Open Med Case Reports. 2016;4:2050313X16666231.
Hughes HK, Rose D, Ashwood P. The Gut Microbiota and Dysbiosis in Autism Spectrum Disorders. Curr Neurol Neurosci Rep. 2018;18:81.
Gurbanov R, Uzun C. Bağırsak Mikrobiyotası Ekseninde Multipl Skleroz: Probiyotiklerin Rolü. In: Oğuz Ö, Lüleyap Ü, Aksu F, eds. Güncel Temel Tıp Bilimleri Çalışmaları I. 1st ed. Ankara, Türkiye: Akademisyen Kitabevi; 2019:83-97.