Autism Spectrum Disorders (ASD) are a group of neurodevelopmental disorders characterized by their behavioral core features, impairment in social communication and social interactions, and restricted, repetitive and stereotyped patterns. Due to heterogeneity, autism has been termed a spectrum disorder. Although genetic mutations play a major role a causative factor in ASD, several environmental risk factors during pregnancy have been associated with the development of autism in children. For instance, trace metal imbalances such as zinc deficiency have been linked to the development of ASD in humans with several studies reporting high incidence rates of zinc deficiency in young ASD patients compared to healthy controls. Underlining the importance of adequate zinc levels during development we created a mouse model in which zinc deficiency of mothers during pregnancy results in an autistic phenotype in offspring1-3.

However, the underlying mechanisms, how zinc deficiency results in ASD, are currently unknown -  a gap we want to close with this proposed project.

Although many autistic children have specific food preferences or sensitivities, it is unlikely that malnutrition in general leads to this high number of zinc deficiencies seen among ASD patients. We thus hypothesize that trace metal imbalances cause disturbances in the gastrointestinal (GI) tract.
A growing amount of research indicates that abnormalities in the GI system during development play a part in ASD. Said GI pathology might serve as a contributing factor in the development of ASD in offspring. Several studies link behavioral difficulties in autistic children to GI abnormalities. In patients in-between 19-70% present with at least one GI symptom. Frequently reported symptoms include an altered intestinal barrier function („leaky gut“).

For possible future therapeutic approaches for ASDs, the essential question of the origin and consequences of the observed dysregulation of trace metal homeostasis needs to be answered. Thus, in line with studies linking ASD to GI disorders in humans, in this project we investigate a potential GI pathology in the prenatal zinc deficient mouse model (PZD) of ASD including morphology assessment, proteomics, and gut microbiomics.
Furthermore, GI alterations may challenge the immune system (intestinal and systemic). Indeed, ASD in humans has been associated with inflammation and immune dysfunction. Therefore, PZD mice are also analyzed regarding their inflammatory status. Moreover, the presence of inflammatory processes in brain tissue will be measured.

The project conducted on mice will not only identify mechanisms how zinc deficiency during pregnancy affects the developing children but also reveal a list of specific biomarkers, including alterations in specific microbiota and peripheral immune markers that in future will allow identification of a subpopulation of a) mothers with mild zinc deficiency, b) offspring subjected to prenatal zinc deficiency, and c) biomarkers for a subpopulation of children with ASD, that can be validated in human studies to improve diagnosis and personalized treatment.

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