CHD8 regulates gut epithelial cell function and affects autism-related behaviors through the gut-brain axis

Abstract Autism is a neurodevelopmental disorder characterized by early-onset social behavioral deficits and repetitive behaviors. Chromodomain helicase DNA-binding protein (CHD8) is among the genes most strongly associated with autism. In addition to the core behavioral symptoms of autism, affected individuals frequently present with gastrointestinal symptoms that are also common among individuals harboring mutations in the gene encoding CHD8. However, little is known regarding the mechanisms whereby CHD8 affects gut function. In addition, it remains unknown whether gastrointestinal manifestations contribute to the behavioral phenotypes of autism. The current study found that mice haploinsufficient for the large isoform of Chd8 (Chd8L) exhibited increased intestinal permeability, transcriptomic dysregulation in gut epithelial cells, reduced tuft cell and goblet cell counts in the gut, and an overall increase in microbial load. Gut epithelial cell-specific Chd8 haploinsufficiency was associated with increased anxiety-related behaviors together with a decrease in tuft cell numbers. Antibiotic treatment of Chd8L haploinsufficient mice attenuated social behavioral deficits. Together, these results suggest Chd8 as a key determinant of autism-related gastrointestinal deficits, while also laying the ground for future studies on the link between GI deficits and autism-related behaviors.