Research reportAutistic-like behavioural and neurochemical changes in a mouse model of food allergy
Introduction
The intestinal tract continuously encounters foreign antigens and is therefore the most complex organ of the immune system. The majority of these antigens are harmless food antigens to which the body has formed a tolerogenic reaction. Genetic predisposition and environmental factors, however, can abrogate tolerance towards food allergens, leading to a Th2-directed immune response characterized by production of allergen-specific immunoglobulins during sensitization, and mast cell degranulation upon a second exposure to the allergen [1].
The intestinal tract is not only distinguished by its crucial immune function, but also exerts an important neurological function and is called ‘the second brain’ because of its abundant amount of enteric nerves. Evidence is emerging that intestinal immune disturbances can signal to the brain through various pathways, affecting behaviour and emotion [2]. Food allergy has been suggested to be one of the intestinal triggers that can contribute to the expression of various psychological and psychiatric traits, including anxiety, depression, migraine, schizophrenia, attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD) [3], [4], [5], [6]. Supporting the hypothesis that food allergy can affect mental disorders of psychosocial relevance, Meldrum et al. [7] recently observed social neurodevelopmental abnormalities in food allergic children at 18 months of age. Diagnosis of food allergy was associated with enhanced internalizing behaviour and a trend towards low social emotional scores. Intestinal problems are often reported in children with ASD [8], [9] and milk intake was found to be a predictor of constipation [10]. Furthermore, a (gluten and) milk protein free diet is suggested to improve autistic behaviours [11], [12], [13] and to restore the increased intestinal permeability observed in these children [14]. Preclinical studies on neurological effects of food allergy are limited. Mice immunized to ovalbumin (OVA) displayed increased anxiety 1 h after oral challenge with OVA [15]. Moreover, c-Fos staining of the paraventricular nucleus (PVN) of the hypothalamus and central nucleus of the amygdala was observed in these mice 90 min after OVA challenge, accompanied by increased serum levels of corticosterone.
Not only food allergy, but also other allergic diseases have been associated with neuropsychological sequelae [7], [16], [17]. Symptoms of developmental and behavioural dysfunction were more frequent in children with asthma compared to control children and asthma severity was shown to correlate with greater behavioural difficulties [16], [18]. In addition, ADHD was positively associated with eczema and asthma [19] and a preliminary report indicated that ASD was more prevalent among children with mastocytosis [20], suggesting a role for mast cell activation in triggering neurological manifestations. Preclinical studies showed that OVA-immunized mice challenged via the airways displayed comparable brain activation as mice challenged via the oral route [15]. Furthermore, allergic rhinitis increased anxiety and reduced social interaction in rats and mice, one day after allergen challenge [21].
Despite these clinical and preclinical indications, there is still much debate on the existence of food allergy-enhanced psychosocial disabilities and the question whether food allergy in mice affects social and repetitive behaviour has never been explored. Therefore, this study investigated the effects of a food allergic immune response on social interactions, repetitive behaviour and spontaneous alternation in mice and examined associated region-specific neuronal activation and monoamine levels.
Section snippets
Cow's milk allergy mouse model
Three-week-old, specific pathogen free, male C3H/HeOuJ mice were purchased at Charles River Laboratories (L’Arbresle Cedex, France) and housed at the animal facility of the Utrecht University on a 12 h light–dark cycle with access to food and water ad libitum. Mice were bred and raised on a cow's milk protein-free diet (Special Diet Services, Witham, UK). All animal procedures were approved by and conducted in accordance with the guidelines of the Animal Ethics Committee of Utrecht University
Allergic response to oral whey challenge in whey-sensitized mice
The allergic response was assessed by measuring mMCP-1 levels as a marker for mucosal mast cell degranulation in serum collected 16 h after challenge. Serum mMCP-1 concentrations were increased in allergic whey-sensitized mice compared to control sham-sensitized mice (P < 0.001, Fig. 2A). Furthermore, levels of whey-specific IgE (P < 0.001, Fig. 2B), IgG1 (P < 0.001, Fig. 2C) and IgG2a (P < 0.001, Fig. 2D) were increased in serum of allergic mice compared to control mice.
Food allergic mice display reduced social interaction and increased repetitive behaviour
To assess the effect of the
Discussion
There is little fundamental evidence showing direct effects of food allergic immune responses on social and repetitive behaviour. In the present study, we showed that an IgE-mediated allergic immune response in the intestinal tract of mice, induced shortly after weaning, is associated with disturbed social interaction, without any overt signs of sickness. This effect was specific for food allergy, as social behaviour was not changed in DSS-induced colitis mice. Notably, the social interaction
Acknowledgements
We thank P.J. Dederen for his technical assistance with the immunohistochemical c-Fos staining, J.G. Veening for sharing his expertise interpreting the c-Fos staining and J. Korkeaviita for counting the initial staining. We thank B.C. van Esch and G.A. Hofman for their assistance with the mouse model for cow's milk allergy.
This study is part of the Utrecht University ‘Focus en Massa’ program and financially supported by Nutricia Research. Dr. S. Lopes da Silva and Prof. Dr. J. Garssen are
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