Movement and Nutrition in Health and Disease

Reissmann et al. Gluten-free and casein-free diets in autism spectrum disorder | 21 Movement and Nutrition in Health and Disease ________________________________________________________________________________________________ Gluten-free and casein-free diets in the management of | Review autism spectrum disorder: A systematic literature review Andreas Reissmann, Joachim Hauser, Ewelina Stollberg, Klaus W. Lange Institute of Psychology, University of Regensburg, 93040 Regensburg, Germany Correspondence: [email protected] Received 10 July 2018; Revised received 11 November 2019; Accepted 17 March 2020; Published 31 March 2020 Abstract: Autism spectrum disorder (ASD) comprises a group of heterogeneous constellations characterized by deficits in cognitive, communicative, and social skills. ASD has no established etiology and the search for reliable biomarkers has proved to be difficult, giving rise to alternative theoretical accounts, including those related to nutrition. One such account posits that the proteins gluten and casein, derived from wheat and milk respectively, are causally involved in the symptomatic expression of the disorder. As a consequence, a diet devoid of such proteins has been hypothesized to ameliorate the behavioral symptoms of children with ASD. The scope of the present review is to analyze the effects of gluten-free and casein-free (GFCF) diets on children with autism. It has been shown that 8‒32% of parents of affected children report the current use of a GFCF diet regimen in their children. The majority of identified dietary intervention studies failed to meet basic methodological standards of interventional science. A comparison of studies conducted with adequate scientific rigor did not show any clear-cut results. In addition to the inconsistent pattern of results, findings of challenge studies largely failed to find behavioral effects after applying gluten/casein challenges to children with ASD. Studies of potential side effects suggest that it is important to monitor both aspects of nutritional adequacy and healthy physical development in children with ASD on a GFCF dietary regimen. In conclusion, evidence for the effectiveness of the GFCF diet in the treatment of autism is sparse. Rigorous scientific evaluations found no convincing evidence of therapeutic effects of the GFCF diet. Nevertheless, more sophisticated investigations should be conducted in order to identify possible benefits and harms of such a dietary approach, particularly in subgroups of individuals with ASD yet to be identified. Keywords: Autism spectrum disorder; complementary and alternative medicine; nutrition; gluten-free and casein-free diets. 1. Introduction which also includes the former diagnostic classes of Autism or autistic disorder represents a group of Asperger syndrome and pervasive developmental heterogeneous constellations characterized by deficits in disorder-not otherwise specified [2]. Autism has been cognitive, communicative, and social skills as well as shown to occur in approximately 0.2% of child and repetitive sensory-motor behaviors [1,2]. The disorder adolescent populations, while prevalence estimates for emerges during childhood and is thought to be a lifelong the whole spectrum average around 0.6% [3]. Prevalence condition. The fifth revision of the Diagnostic and estimates have been shown to have risen over the last two Statistical Manual of Mental Disorders introduced the decades. The prevalence rates of autistic disorder before umbrella diagnosis of autism spectrum disorder (ASD), 1987 did not exceed 0.07%, whereas all studies published Movement and Nutrition in Health and Disease 2020; 4: 21−38 | DOI: 10.5283/mnhd.9 Reissmann et al. Gluten-free and casein-free diets in autism spectrum disorder | 22 since 2000 have consistently shown higher rates (range the biomarkers identified to date have proven either 0.07‒0.4%). While this rise in prevalence might be sensitive for the identification of autism (presence of attributed to a concomitant rise in the incidence of the biomarker reliably predicts occurrence of disorder) or disorder, other factors, such as changes in the concepts specific for autism (presence readily distinguishes autism and diagnostic criteria as well as a growing awareness in from other disorders or healthy groups). This hinders the Western societies, have been put forward as alternative development of causal therapeutic approaches as well as explanations [3]. In regard to the etiology of ASD, more the development of routinely administered biological biologically oriented accounts have suggested the diagnostic procedures [8]. It is likely that autism is a highly involvement of exposure to certain risk-inducing complex disorder with multiple causative pathways environmental agents and have also discussed the involved in its etiology. If this is the case, the identification potential role of nutrition within a “gene x environment” of reliable biomarkers for routine use in diagnosis and framework (see reference 4). From this point of view, an intervention may be impossible. Therefore, current unbalanced diet could potentially induce biological treatment approaches to autism should be regarded as vulnerability, or an otherwise balanced diet might disturb symptomatic, as they aim to improve the core deficits the organism’s homeostasis in the case of metabolic associated with the disorder in order to optimize the insufficiency [4]. Whether such an explanatory model is outcome of affected children (see reference 1). valid is a matter of ongoing debate [5], which has No biomarkers of the disorder have as yet been continued, in recent decades, against the background of identified [8]. Several different etiological accounts world-wide changes in dietary habits, including higher therefore coexist. The “opioid excess theory”, proposed intake of unhealthy fats and lower intake of fiber [6]. by Panksepp [9], draws parallels between the disorder’s Suggestive evidence such as this should be treated with symptoms and the acute behavioral effects of opiates, i.e. caution, however, and should be integrated with current the disorder is linked to increased activity in the knowledge regarding the etiology of autism. endogenous opioid system. On the basis of this Etiological accounts of autism place heavy emphasis suggestion, Reichelt et al. [10,11] were able to on biological factors in regard to both the organism demonstrate a possible nutritional link to autism, (genes) and the environment (e.g. exposure to neurotoxic theorizing that certain food proteins, such as gluten and agents) and seek to link the influence of these factors to casein, can be transformed to opioid peptides during confirmed biomarkers of brain and organismic function digestion. These peptides, hypothesized to be [1,7,8]. Potential biomarkers of autism may include metabolized insufficiently, were suggested to accumulate structural brain abnormalities (e.g. increase in brain and hence to be able to enter the blood stream through a volume, especially in frontal cortex, cerebellum and “leaky gut”, i.e. an increased permeability of the intestinal amygdala), functional brain abnormalities (e.g. dis- membrane [12]. Through systemic circulation, these connectivity of cortical structures with more asynchrony peptides might cross the blood-brain barrier and act in activity; abnormal levels of neurotransmitters and directly upon the central nervous system [13]. As such an neuropeptides) as well as more systemic indicators account conceptualizes autism as a disorder of the “gut- related to metabolism (e.g. indicators of mitochondrial brain-axis” [14], the account predicts heightened urinary dysfunction, abnormal urinary excretion of organic acids) peptide levels of these opioid peptides as a biomarker of and indicators of an increased dysregulation of immune the disorder. As a therapeutic consequence, a diet low in functions [7]. These observations are complemented by such proteins was hypothesized to normalize the urinary findings demonstrating an association between the peptide levels and hence to ameliorate the behavioral occurrence of the disorder and polymorphisms of genes symptoms of affected children [10,13]. Another prediction related to cell structure and function, neuronal pertains to the presumed increased permeability of the development and synaptic formation as well as with genes intestinal membrane, allowing for systemic entry of food- involved in neurotransmission [7]. There are also derived opioid-like peptides. indications of an increase in prevalence of autism Preclinical evaluations of central nervous system following exposure to certain environmental agents such effects of these food-derived peptides (e.g. β- as pesticides and solvents, which could potentially affect casomorphine) using rodent models were able to show brain development [7]. The search for biomarkers has led behavioral effects such as a reduction in pain sensitivity, to some progress in the field. However, there are as many motor activity, and (social) orientation [15,16]. Other problems as there are answers (see reference 8): none of studies failed to show acute behavioral effects of gluten- Movement and Nutrition in Health and Disease 2020; 4: 21−38 | DOI: 10.5283/mnhd.9 Reissmann et al. Gluten-free and casein-free diets in autism spectrum disorder | 23 or casein-derived opioid peptides [17‒20], while others clusters according to their design and the outcome found evidence for lasting behavioral changes following measures used. A total of 16 dietary

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