THE GUT-IMMUNE PHENOTYPE IN NEURODEVELOPMENTAL DISORDERS

Abstract

Diverse clinical presentation in neurodevelopmental disorders (NDDs) leads to difficulty in matching individuals with effective treatments. Autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD) are the two most prevalent neurodevelopmental disorders (NDDs), characterized by deficits in communication, social interactions, and behaviours. There is high within-diagnosis heterogeneity and striking overlap between diagnoses. The literature suggests that current diagnostic criteria do not align well with behaviour metrics. Therefore, identifying novel biomarkers underlying behaviour in NDDs may provide a reliable way to group individuals with similar behavioural phenotypes. This thesis examines how gut-immune biology is linked to clinical heterogeneity in children with NDDs. The first study used unsupervised machine learning to cluster typically developing (TD), ADHD, and ASD participants by their behaviour metrics in a diagnosis-agnostic approach. The results produced a six-cluster solution, five of which were a mix of all diagnostic categories. Further, gastrointestinal (GI) symptoms were mapped to the clusters, revealing a link between constipation, social communication deficits and restrictive-repetitive behaviours. The second study used hierarchical clustering to group TD and NDD participants based on a profile of gut and inflammatory markers. Participants clustered into two biotypes, both containing TD and NDD participants. Additionally, using regression analysis, novel markers were linked to anxiety. The third study evaluated the multisite biospecimen collection protocol of the Province of Ontario Neurodevelopmental Disorders (POND) Network. The final study used biospecimens collected from the POND network to phenotype peripheral blood mononuclear cells in TD and NDD participants. In NDD groups, monocyte and B cell activation markers were differentially expressed compared to TD. Overall, this thesis demonstrates that gut-immune mechanisms contribute to clinical heterogeneity in a subset of people and contribute to the search for biomarkers in NDDs.