- Awarded: 2019
- Award Type: Pilot
- Award #: 645766
Gastrointestinal issues have been identified as a comorbidity of autism spectrum disorder (ASD). Yet, the connection between ASD and gastrointestinal issues is not clear, and it is also not clear if gastrointestinal dysfunction plays a role in the development or severity of the core behavioral symptoms of ASD. There are several subgroups of individuals with ASD that are known to have a particularly high prevalence of gastrointestinal issues. Such issues have been found in individuals with specific autism-associated genetic mutations. For example, many individuals with CHD8 mutations report gastrointestinal issues1.
CHD8 has been identified as a highly penetrant risk factor for ASD based on human genetic studies. Further, mouse models have verified that Chd8, a chromatin binding protein, plays a critical role in social behavior and neurodevelopment2–4. There is also preliminary evidence from zebrafish models of Chd8 haploinsufficiency that Chd8 is important for normal gut functions. Nonetheless, how Chd8 regulates gastrointestinal function, and if there is a connection between such issues and core behavioral symptoms of ASD, is not known.
Evan Elliott and colleagues have preliminary findings suggesting that Chd8 haploinsufficient mice display increased gut permeability. Considering that permeability is related to epithelial cell function, they further isolated gut epithelial cells from wild type and mutant mice and performed RNA-seq analysis. Robust differences in the expression profiles of epithelial cells were found in mutant mice compared to wild type. Remarkably, these differences were much more robust than the effects of Chd8 haploinsufficiency on gene expression in the brain. In particular, a marked decrease in the expression of genes specifically expressed in Tuft cells — specialized epithelial cells involved in immune responses and gut permeability — were observed.
In the current study, Elliott and his team aim to fully characterize the gastrointestinal, immune and metabolic phenotype of Chd8 haploinsufficient mice, to determine the mechanistic link between Chd8 and gut function, and to study if Chd8 dysfunction in the gut correlates with behavioral symptoms of relevance to ASD. As an additional goal, they plan to induce a specific knockdown of Chd8 in the gut, and then test these mice for gut and behavioral abnormalities. This will give important insight into the relationship between gut dysfunction and behavioral changes relevant to ASD as well as establishing the importance of the gut-brain axis in this condition.
Overall, this project aims to understand how genetic predisposition to ASD affects gut function, as well as leading to a better understanding of the role of gut dysfunction in biological, physiological and behavioral changes relevant to ASD.