Neuroimmunomodulation of the young brain. Nutrition, a gut feeling

Abstract

Neurodevelopmental disorders, such as autism spectrum disorder (ASD), are heterogeneous conditions, in which both genetic predisposition and environmental factors play a role. Prenatal environmental factors such as maternal immune activation, deficient nutrition, and drugs use during pregnancy increase the risk of neurodevelopmental disorders in the newborn. Also during postnatal development, environmental factors can have a persistent impact on brain development. It is hypothesized that (allergic) immune activation, particularly in the intestines, contributes to the behavioural impairments in ASD. Although gastrointestinal problems are frequently reported in patients with ASD, the importance of the gut-brain axis in ASD is still under debate. This thesis was aimed to gain more insight on comorbid intestinal problems in ASD and the effects of (allergic) immune activation on neurochemical systems and on behaviour relevant to ASD. This thesis provides evidence for male-specific occurrence of intestinal inflammation and dysbiosis of the microbiome in a mouse model for ASD, using prenatal exposure to valproic acid (VPA). Moreover, it demonstrates that serotonergic changes in the brain of VPA-exposed mice are highly correlated to those observed in the intestines, implying that a common serotonergic deficit may underlie behavioural and intestinal problems. Both behavioural and serotonergic impairments in VPA-exposed mice are normalized when VPA-exposed mice are fed a pre- and postnatal diet containing specific anti-inflammatory and neuroprotective ingredients. Hence, this diet may be effective as supplementation during pregnancy or early in life, in reducing the risk of neurodevelopmental disorders. Furthermore, this thesis demonstrates that food allergy in mice leads to reduced social interaction and increased repetitive behaviour as well as it alters the mesocorticolimbic dopamine system and neuronal activation in the prefrontal cortex and the paraventricular nucleus of the hypothalamus. Nutritional supplementation with n-3 long chain polyunsaturated fatty acids in food allergic mice prevents impairments in social behaviour and in the dopaminergic system. Disturbed social interaction and repetitive behaviour in food allergic mice are also prevented by the diet that contained specific anti-inflammatory and neuroprotective ingredients. Finally, this thesis shows that prenatal exposure to VPA alters the allergic response, characterized by an increased polarization of the immune response towards Th2. Therefore, individuals exposed to neurodevelopmental risk factors in utero may be predisposed to develop allergic diseases later in life. Together, the findings in this thesis create more insight into the occurrence of intestinal inflammation during impaired neurodevelopment and the effects of food allergy on the developing brain. Moreover, it demonstrates that nutritional interventions may be beneficial in the prevention or management of impaired neurodevelopment.