Serum Zonulin, Gut Permeability, and the Pathogenesis of Autism Spectrum Disorders: Cause, Effect, or an Epiphenomenon?
2017; Elsevier BV; Volume: 188; Linguagem: Inglês
10.1016/j.jpeds.2017.05.038
ISSN1097-6833
Autores Tópico(s)Infant Health and Development
ResumoSee related article, p 240 See related article, p 240 Autism is not a single disorder, but a spectrum of related disorders (autism spectrum disorders [ASD]) with a shared core of symptoms defined by deficits in communication, social reciprocity, and repetitive, stereotypic behaviors. Following recognition in the mid 1940s by Kanner and Asperger, theories to explain the cause of ASD have evolved. Initially, inborn biologic and psychogenic factors were implicated.1Kanner L. Irrelevant and metaphorical language in early infantile autism.Am J Psychiatry. 1946; 103: 242-246Crossref PubMed Scopus (185) Google Scholar, 2Asperger H. Psychotherapie in der Pädiatrie.Osterr Z Kinderheilkd Kinderfuersorge. 1948; 2: 17-25PubMed Google Scholar In support of a biologic theory, Rimland3Rimland B. On the objective diagnosis of autism.Acta Paedopsychiatr. 1968; 35: 146-161PubMed Google Scholar outlined a cogent 9-point argument favoring biologic over psychogenic causes. This reasoning was in contrast with Bettelheum who had previously proposed a psychogenic cause in his "the empty fortress" publication in which he asserted that "refrigerator mothers" were the primary cause of ASD.4Bettelheum B. Sylvester E. Notes on the impact of parental occupations: some cultural determinants of symptom choice in emotionally disturbed children.Am J Orthopsychiatry. 1950; 20: 785-795Crossref PubMed Scopus (2) Google Scholar By publishing the first autism twin study in the early 1980s, Folstein and Rutter5Folstein S. Rutter M. Infantile autism: a genetic study of 21 twin pairs.J Child Psychol Psychiatry. 1977; 18: 297-321Crossref PubMed Scopus (945) Google Scholar were the first to suggest a heritable component of ASD. Lately, as for many other chronic nontransmissible diseases, it has been hypothesized that ASD is the result of gene–environment interactions. In support of this postulate is the observation that the prevalence of ASD has increased 35-fold since the earliest epidemiologic studies conducted in the late 1960s and early 1970s, and now represents a significant public health problem affecting approximately 1 in 68 children worldwide. The reasons for the increased prevalence are unclear, but may in part be owing to improved awareness and recognition of the condition as well as changes in diagnostic practice and service availability.6Blumberg S.J. Bramlett M.D. Kogan M.D. Schieve L.A. Jones J.R. Lu M.C. Changes in prevalence of parent-reported autism spectrum disorder in school-aged US children: 2007 to 2011-2012.Nat Health Stat Reports. 2013; 65: 1-12PubMed Google Scholar However, other environmental factors are probably at play to explain this "epidemic." Based on the gene–environment interaction theory, several treatment approaches have been proposed with conflicting and sometimes completely opposite results.7Fletcher-Watson S. McConnell F. Manola E. McConachie H. Interventions based on the Theory of Mind cognitive model for autism spectrum disorder (ASD).Cochrane Database Syst Rev. 2014; (CD008785)PubMed Google Scholar, 8Sukhodolsky D.G. Bloch M.H. Panza K.E. Reichow B. Cognitive-behavioural therapy for anxiety in children with high-functioning autism: a meta-analysis.Pediatrics. 2013; 132: e1341-50Crossref PubMed Scopus (145) Google Scholar, 9Millward C. Ferriter M. Calver S. Connell-Jones G. Gluten-and casein-free diets for autistic spectrum disorder.Cochrane Database Syst Rev. 2008; (CD003498)PubMed Google Scholar This is likely due to the fact that ASD, like many other multifactorial disorders, is a final destination that can be reached through multiple different pathways. Many individuals with ASD have symptoms of associated comorbidities, including seizures, sleep problems, metabolic conditions, and gastrointestinal (GI) disorders, which have significant health, developmental, social, and educational impacts. The underlying mechanisms of GI dysfunction in children with ASD are yet to be convincingly elucidated. Previously, endoscopies in some children with ASD and GI symptoms were reported to show inflammation of the intestinal tract described as a sort of "ASD colitis."10Wakefield A.J. Murch S.H. Anthony A. Linnell J. Casson D.M. Malik M. et al.Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children.Lancet. 1998; 351: 637-641Abstract Full Text Full Text PDF PubMed Scopus (1819) Google Scholar These findings have become highly controversial, because the original studies from Wakefield et al10Wakefield A.J. Murch S.H. Anthony A. Linnell J. Casson D.M. Malik M. et al.Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children.Lancet. 1998; 351: 637-641Abstract Full Text Full Text PDF PubMed Scopus (1819) Google Scholar linking the onset of ASD and related colitis to the measles, mumps, and rubella vaccination were cited for overinterpretation of data obtained from a very limited number of children, and subsequently resulted in the retraction of the original manuscript.11Eggertson L. Lancet retracts 12-year-old article linking autism to MMR vaccines.CMAJ. 2010; 182: E199-200Crossref PubMed Scopus (132) Google Scholar Although the link with the measles, mumps, and rubella vaccination has been refuted and the severity and frequency of intestinal inflammation in children with ASD is considered far less than reported by Wakefield et al, there is evidence of low-grade GI inflammation in a subgroup of children with ASD.12Kushak R.I. Buie T.M. Murray K.F. Newburg D.S. Chen C. Nestoridi E. et al.Evaluation of intestinal function in children with autism and gastrointestinal symptoms.J Pediatr Gastroenterol Nutr. 2016; 62: 687-691Crossref PubMed Scopus (47) Google Scholar The precise nature of this inflammation is unclear but histology, immunohistochemistry, and flow cytometry have shown a pan-enteric infiltration of immune cells in the walls of the GI tract in children with ASD and GI symptoms, that is not present in neurotypical children with similar GI symptoms.13Coury D.L. Ashwood P. Fasano A. Fuchs G. Geraghty M. Kaul A. et al.Gastrointestinal conditions in children with autism spectrum disorder: developing a research agenda.Pediatrics. 2012; 130: S160-8Crossref PubMed Scopus (172) Google Scholar Another fascinating, yet unsettled, debate regarding the involvement of the GI tract in the pathogenesis of ASD is the possible role played by the loss of gut barrier function that has been detected in some children with ASD. In this volume of The Journal, Esnfoglu et al14Esnafoglu E. Cırrık S. Ayyıldız S.N. Erdil A. Ertürk E.Y. Daglı A. et al.Increased serum zonulin levels as an intestinal permeability marker in autistic subjects.J Pediatr. 2017; 188: 240-244Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar used serum zonulin as a biomarker of gut permeability in subjects with ASD. Zonulin has been linked to a variety of chronic inflammatory diseases and its release has been associated with several environmental stimuli, including gluten and microbiome dysbiosis,15Sturgeon C. Fasano A. Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inflammatory diseases.Tissue Barriers. 2016; 4: e1251384Crossref PubMed Scopus (229) Google Scholar both also reported to be implicated in ASD pathogenesis. The authors found that zonulin was increased in patients with ASD compared with healthy controls and that there was a positive correlation identified between serum zonulin levels and a childhood autism rating scale. In line with these results, a recent study reported that 33% of children with ASD tested positive for serum IgA antibodies against CXCR3-binding gliadin peptide,16Vojdani A. Vojdani E. Gluten and not-gluten proteins of wheat as target antigensin autism, Crohn's disease, and celiac disease.J Cer Sci. 2017; 75 (online available ahead print April 21): 252-260Crossref Scopus (4) Google Scholar the gliadin fragment shown to trigger zonulin release by binding to the CXCR3 receptor.17Lammers K.M. Lu R. Brownley J. Lu B. Gerard C. Thomas K. et al.Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3.Gastroenterology. 2008; 135: 194-204Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar Gut permeability in ASD is a highly debated topic and its role in the pathogenesis of the disease, rather than being the consequence or merely an epiphenomenon, remains highly controversial. Recent evidence from animal18Hsiao E.Y. McBride S.W. Hsien S. Sharon G. Hyde E.R. McCue T. et al.Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders.Cell. 2013; 155: 1451-1463Abstract Full Text Full Text PDF PubMed Scopus (2041) Google Scholar and human studies19Fiorentino M. Sapone A. Senger S. Camhi S.S. Kadzielski S.M. Buie T.M. et al.Blood-brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders.Mol Autism. 2016; 7 (eCollection 2016): 49Crossref PubMed Scopus (226) Google Scholar suggest a bidirectional communication between the gut and the brain, linking a microbiome-induced increased gut permeability to exaggerated entry of commensal bacteria into the bloodstream where they could stimulate faulty immune regulation and, ultimately, neuroinflammation typical of ASD. Indeed, there is growing evidence suggesting that the neuroanatomic and biochemical characteristics associated with ASD pathogenesis20Zielinski B.A. Prigge M.B. Nielsen J.A. Froehlich A.L. Abildskov T.J. Anderson J.S. et al.Longitudinal changes in cortical thickness in autism and typical development.Brain. 2014; 137: 1799-1812Crossref PubMed Scopus (243) Google Scholar, 21Stoner R. Chow M.L. Boyle M.P. Sunkin S.M. Mouton P.R. Roy S. et al.Patches of disorganization in the neocortex of children with autism.N Engl J Med. 2014; 370: 1209-1219Crossref PubMed Scopus (476) Google Scholar, 22Rossignol D.A. Frye R.E. A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures.Mol Psychiatry. 2012; 17: 389-401Crossref PubMed Scopus (347) Google Scholar involve mechanisms that are direct consequences, or can exacerbate the effects, of low-grade, feverless, systemic inflammatory events,23Nankova B.B. Agarwal R. MacFabe D.F. La Gamma E.F. Enteric bacterial metabolites propionic and butyric acid modulate gene expression, including CREB-dependent catecholaminergic neurotransmission, in PC12 cells-possible relevance to autism spectrum disorders.PLoS ONE. 2014; 9 (e103740)Crossref PubMed Scopus (148) Google Scholar, 24MacFabe D. Autism: metabolism, mitochondria, and the microbiome.Glob Adv Health Med. 2013; 2: 52-66Crossref PubMed Google Scholar whereas the mechanisms protective against ASD pathogenesis have strong anti-inflammatory components.25Scumpia P.O. Kelly-Scumpia K. Stevens B.R. Alpha-lipoic acid effects on brain glial functions accompanying double-stranded RNA antiviral and inflammatory signaling.Neurochem Int. 2014; 64: 55-63Crossref PubMed Scopus (19) Google Scholar Nevertheless, using other biomarkers of gut permeability, including sugar probes, researchers have obtained inconsistent results.12Kushak R.I. Buie T.M. Murray K.F. Newburg D.S. Chen C. Nestoridi E. et al.Evaluation of intestinal function in children with autism and gastrointestinal symptoms.J Pediatr Gastroenterol Nutr. 2016; 62: 687-691Crossref PubMed Scopus (47) Google Scholar, 26de Magistris L. Familiari V. Pascotto A. Sapone A. Frolli A. Iardino P. et al.Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives.J Pediatr Gastroenterol Nutr. 2010; 51: 418-424Crossref PubMed Scopus (364) Google Scholar Hence, the loss of gut barrier function may not be a generalizable phenomenon among children with ASD, but instead could involve only a subgroup of patients. This consideration should caution against the temptation to rush to the conclusion that fixing gut permeability would efficiently treat all cases of ASD. Rather, by contributing to the ongoing debate, this article should stimulate other researchers to expand these results in larger cohorts to eventually validate serum zonulin as an additional and simpler biomarker for gut permeability to be used both by basic scientists and clinicians to gain more insight into the pathogenesis of ASD and potential new treatments. Increased Serum Zonulin Levels as an Intestinal Permeability Marker in Autistic SubjectsThe Journal of PediatricsVol. 188PreviewTo evaluate the serum levels of zonulin, which regulates tight junctions between enterocytes and is a physiological modulator controlling intestinal permeability, in patients with autism spectrum disorders (ASDs). Full-Text PDF
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