Nietolerancja glutenu w spektrum autyzmu ?

W literaturze medycznej pojawiają się ciągle nowe informacje na temat przyczyn lub czynników ryzyka powiązanych z autyzmem. Koncepcji jest wiele, od czysto somatycznych podnoszących jedynie biologiczne podłoże problemu, po czysto duchowe wynikające z karmy czy przekleństwa pokoleniowego. Bez względu na to jaka jest przyczyna tego problemu,  rodzice dzieci z autyzmem czekają na nowe możliwości terapeutyczne. Niewątpliwe, uwzględniając jedynie koncepcje biologiczne, najważniejszą kwestią jest poznanie przyczyn problemu i czy można je modyfikować. Główne kontrowersje dotyczą kwestii czy autyzm jest nabyty poprzez ekspozycję na czynniki zewnętrzne, czy może jest jedynie realizacją programu genetycznego ? Im więcej niejasności tym więcej pola do popisu dla teorii spiskowych. Numerem jeden jest oczywiście powiązanie szczepionek ze zwiększeniem ryzyka występowania autyzmu. Na podstawie twardych dowodów naukowych nie ma powiązania, że zdecydowanie szczepionki szkodzą, ale nie ma też dowodu, który jednoznacznie obalałby ten pogląd. Przeprowadzenie badania o najwyższym stopniu wiarygodności naukowej w sprawie szkodliwości szczepionek naukowej jest prawdopodobnie niemożliwe. Główny problem to  selekcja czynników ryzyka, które są mnogie i sprowadzenie wniosków końcowych do odpowiedzi TAK czy NIE w sprawie szczepionek jest raczej niemożliwe. Druga trudność to podział dzieci na te szczepione i nieszczepione przy założeniu, że badanie wymagałaby rekrutacji tysięcy dzieci w każdej grupie i ….. kto zgodziłby się aby nie szczepić własnych dzieci.

Wracając, do biologicznych przyczyn autyzmu, raczej mało prawdopodobne jest, aby tylko jeden czynnik mógł wywoływać to zaburzenie.  Wydaje się, że cały sekret kryje się w swoistej zmienności układu immunologicznej, który prawdopodobnie nabywa pewną odmienność poprzez ekspozycję na antygeny zewnętrzne i moduluje swoją aktywność wobec niedojrzałego mózgowia, a szczególnie układu limbicznego.

Poniżej list ekspertów w sprawie powiązania autyzmu z ekspozycją na gluten i występowaniem chronicznego stanu zapalnego jelit. Podsumowuje on w którym miejscu jesteśmy i dość rozsądnie punktuje obecną wiedzę.

 

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Serum Zonulin, Gut Permeability, and the Pathogenesis of Autism Spectrum Disorders: Cause, Effect, or an Epiphenomenon? 

The Journal of Pediatrics September 2017 vol 188 p 15-17 

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.1,2 In support of a biologic theory, Rimland3 out- lined 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.4 By publishing the first autism twin study in the early 1980s, Folstein and Rutter5 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 world- wide. 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. 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.7-9 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 re- ported to show inflammation of the intestinal tract described as a sort of “ASD colitis.”10 These findings have become highly controversial, because the original studies from Wakefield et al10 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.11 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.12 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.13

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 al14 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,15 both also re- ported to be implicated in ASD pathogenesis. The authors found that zonulin was increased in patients with ASD com- pared with healthy controls and that there was a positive cor- relation 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,16 the gliadin fragment shown to trigger zonulin release by binding to the CXCR3 receptor.17

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 con- troversial. Recent evidence from animal18 and human studies19 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 regu- lation and, ultimately, neuroinflammation typical of ASD. Indeed, there is growing evidence suggesting that the neuroanatomic and biochemical characteristics associated with ASD pathogenesis20-22 involve mechanisms that are direct con- sequences, or can exacerbate the effects, of low-grade, feverless, systemic inflammatory events,23,24 whereas the mechanisms protective against ASD pathogenesis have strong anti-inflammatory components.25

Nevertheless, using other biomarkers of gut permeability, including sugar probes, researchers have obtained inconsistent results.12,26 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. ■

Alessio Fasano, MD

Harvard Medical School Division of Pediatric Gastroenterology and Nutrition and Mucosal Immunology and Biology Research Center Massachusetts General Hospital for Children Boston, Massachusetts

Ivor Hill, MD

The Ohio State University College of Medicine Gastroenterology Nationwide Children’s Hospital Columbus, Ohio

Reprint requests: Ivor Hill, MD, Pediatric Gastroenterology, Nationwide Children’s Hospital, 700 Children’s Drive, Medical Center Blvd, Columbus, OH 43205-2696. E-mail: Ivor.Hill@nationwidechildrens.org

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