Gut-brain interactions in Autism: A multi-modal investigation of the brain, bacteria and behavior

Autism is a neurodevelopmental condition characterized by difficulties with social communication and interaction, combined with restricted and repetitive behaviors and interests. In addition to these core symptoms, individuals with autism often experience a range of co-occurring conditions, including attachment difficulties, social stress and anxiety, as well as gastrointestinal problems and poor oral health. Recent research suggests that gut and oral microbiome compositions may contribute to the etiology of autism, although the specific bacteria involved remain unclear. Furthermore, alterations in the brain's oxytocinergic system play a significant role in the social and stress-regulatory difficulties of autism, with intranasal oxytocin being explored as a therapeutic option. While still in its early stages, preclinical evidence indicates significant bidirectional interactions between the oxytocinergic system and gut and oral microbiota. However, to date, only one study has investigated the effects of intranasal oxytocin on microbiome compositions. The overarching aim of this thesis was to investigate the role of oral and gut microbiome compositions in the underlying mechanisms of autism, their link to clinical characteristics and the endogenous oxytocinergic system, and their potential modulation by intranasal oxytocin administration. This thesis identified diagnosis-related differences in both oral and gut microbiome compositions, with significant associations to behavioral difficulties, even after accounting for lifestyle factors. It also demonstrated that both oral and gut microbiome compositions were linked to brain connectivity, and the potential relevance of microbiome-brain interactions in explaining behavioral difficulties. Furthermore, reduced endogenous oxytocin levels were observed in autistic children, and associations were found between endogenous oxytocinergic signaling and both oral and gut microbiome compositions. Additionally, a four-week course of intranasal oxytocin administration altered both oral and gut microbiome compositions, providing preliminary evidence for the therapeutic potential of oxytocin in modulating microbiome alterations. The insights gained from this thesis provide preliminary evidence supporting the potential utility of oral and gut microbiome alterations as diagnostic markers for autism, and as targets for the development of novel therapeutic strategies.