Elsevier

Behavioural Brain Research

Volume 261, 15 March 2014, Pages 265-274
Behavioural Brain Research

Research report
Autistic-like behavioural and neurochemical changes in a mouse model of food allergy

https://doi.org/10.1016/j.bbr.2013.12.008Get rights and content

Highlights

  • Food allergy in mice reduced social behaviour, increased repetitive behaviour and impaired spatial memory.

  • Abnormalities of the serotonergic system in the intestines occurred.

  • c-Fos expression increased in obitofrontal cortex and decreased hypothalamic paraventricular nucleus.

  • Dopaminergic system was dampened in prefrontal cortex and enhanced in amygdala.

Abstract

Food allergy has been suggested to contribute to the expression of psychological and psychiatric traits, including disturbed social behaviour and repetitive behaviour inherent in autism spectrum disorders (ASD). Most research in this field receives little attention, since fundamental evidence showing direct effects of food allergic immune responses on social behaviour is very limited. In the present study, we show that a food allergic reaction to cow's milk protein, induced shortly after weaning, reduced social behaviour and increased repetitive behaviour in mice. This food allergic reaction increased levels of serotonin (5-hydroxytryptamine; 5-HT) and the number of 5-HT positive cells, and decreased levels of 5-hydroxyindoleacetic acid (5-HIAA) in the intestine. Behavioural changes in food allergic mice were accompanied by reduced dopaminergic activity in the prefrontal cortex. Furthermore, neuronal activation (c-Fos expression) was increased in the prefrontal cortex and reduced in the paraventricular nucleus of the hypothalamus after exposure to a social target. We hypothesize that an intestinal allergic response regulates complex, but critical, neuroimmune interactions, thereby affecting brain circuits involved in social interaction, repetitive behaviour and cognition. Together with a genetic predisposition and multiple environmental factors, these effects of allergic immune activation may exacerbate behavioural abnormalities in patients with ASD.

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

References (77)

  • P.P. Bertrand et al.

    Serotonin release and uptake in the gastrointestinal tract

    Auton Neurosci

    (2010)
  • R. Mossner et al.

    Modulation of serotonin transporter function by interleukin-4

    Life Sci

    (2001)
  • N.S. Coleman et al.

    Abnormalities of serotonin metabolism and their relation to symptoms in untreated celiac disease

    Clin Gastroenterol Hepatol

    (2006)
  • S.P. Dunlop et al.

    Abnormalities of 5-hydroxytryptamine metabolism in irritable bowel syndrome

    Clin Gastroenterol Hepatol

    (2005)
  • R.J. Phillips et al.

    Age-related changes in vagal afferents innervating the gastrointestinal tract

    Auton Neurosci

    (2010)
  • N. Castex et al.

    c-Fos expression in specific rat brain nuclei after intestinal anaphylaxis: involvement of 5-HT3 receptors and vagal afferent fibers

    Brain Res

    (1995)
  • H. van der Kleij et al.

    Evidence for neuronal expression of functional Fc (epsilon and gamma) receptors

    J Allergy Clin Immunol

    (2010)
  • A. Rijnierse et al.

    Immunoglobulin free light chains reduce in an antigen-specific manner the rate of rise of action potentials of mouse non-nociceptive dorsal root ganglion neurons

    J Neuroimmunol

    (2013)
  • K.A. Young et al.

    The role of mesocorticolimbic dopamine in regulating interactions between drugs of abuse and social behavior

    Neurosci Biobehav Rev

    (2011)
  • E. Neuhaus et al.

    Neurobiological correlates of social functioning in autism

    Clin Psychol Rev

    (2010)
  • M. Ernst et al.

    Low medial prefrontal dopaminergic activity in autistic children

    Lancet

    (1997)
  • S. Cabib et al.

    Behavioral and mesocorticolimbic dopamine responses to non aggressive social interactions depend on previous social experiences and on the opponent's sex

    Behav Brain Res

    (2000)
  • X. Han et al.

    Isolation rearing alters social behaviors and monoamine neurotransmission in the medial prefrontal cortex and nucleus accumbens of adult rats

    Brain Res

    (2011)
  • C.R. Li et al.

    Effects of 6-hydroxydopamine lesioning of the medial prefrontal cortex on social interactions in adolescent and adult rats

    Brain Res

    (2010)
  • A. Ziomber et al.

    Chronic impairment of the vagus nerve function leads to inhibition of dopamine but not serotonin neurons in rat brain structures

    Pharmacol Rep

    (2012)
  • J. Bachevalier et al.

    The orbitofrontal–amygdala circuit and self-regulation of social–emotional behavior in autism

    Neurosci Biobehav Rev

    (2006)
  • N. Schmitz et al.

    Neural correlates of executive function in autistic spectrum disorders

    Biol Psychiatry

    (2006)
  • A.R. Damasio et al.

    Individuals with sociopathic behavior caused by frontal damage fail to respond autonomically to social stimuli

    Behav Brain Res

    (1990)
  • J. Hornak et al.

    Face and voice expression identification in patients with emotional and behavioural changes following ventral frontal lobe damage

    Neuropsychologia

    (1996)
  • A.S. Basso et al.

    Neural correlates of IgE-mediated food allergy

    J Neuroimmunol

    (2003)
  • M. Heinrichs et al.

    Oxytocin, vasopressin, and human social behavior

    Front Neuroendocrinol

    (2009)
  • C. Modahl et al.

    Plasma oxytocin levels in autistic children

    Biol Psychiatry

    (1998)
  • F. Sanna et al.

    Oxytocin-induced yawning: sites of action in the brain and interaction with mesolimbic/mesocortical and incertohypothalamic dopaminergic neurons in male rats

    Horm Behav

    (2012)
  • H. Jyonouchi

    Food allergy and autism spectrum disorders: is there a link

    Curr Allergy Asthma Rep

    (2009)
  • G. Addolorato et al.

    Anxiety and depression: a common feature of health care seeking patients with irritable bowel syndrome and food allergy

    Hepatogastroenterology

    (1998)
  • K. Alpay et al.

    Diet restriction in migraine, based on IgG against foods: a clinical double-blind, randomised, cross-over trial

    Cephalalgia

    (2010)
  • L.M. Pelsser et al.

    ADHD as a (non) allergic hypersensitivity disorder: a hypothesis

    Pediatr Allergy Immunol

    (2009)
  • R.A. Smith et al.

    Are there more bowel symptoms in children with autism compared to normal children and children with other developmental and neurological disorders: a case control study

    Autism

    (2009)
  • Cited by (53)

    View all citing articles on Scopus
    View full text