Autism Gene CHD8 Regulates Immune Inflammatory Response In Embryonic Gut

Autism Spectrum Disorder(ASD)is a neurodevelopmental disorder whose prevalence has increased dramatically in the last few decades.Although a great number of researches have been conducted in recent years,the etiology and pathogenesis of ASD are still not fully understood and there are no medications or treatments for core symptoms.ASD is highly hereditary,and a large number of risk genes have been identified,as well as many non-genetic factors such as environmental,metabolic,and immunological factors.The gut is an important site for integrating these genetic and non-genetic factors,but its effects on the etiology and pathology of ASD are yet to be investigated.There is growing evidence that gastrointestinal dysfunction is frequent in individuals with autism and that the severity of gastrointestinal dysfunction is significantly associated with the severity of autism symptoms.To clarify how the gut integrates genetic and non-genetic factors involved in the etiology and pathology of ASD,we investigated the role of risk genes in the gut using a zebrafish autism model.CHD8 is a recently identified high-risk gene for ASD,and more than half of patients carrying mutations in this gene have severe gastrointestinal problems.In the present study,we found that chd8 defects affect the early development of the Intestines,resulting in excessive accumulation of free oxygen radicals in the intestines.Real-time observations of transgenic-labeled immune cells and histochemical staining revealed large aggregations of macrophages and neutrophils in embryonic intestines of chd8-deficient individuals and infiltration of immune cells into the intestinal epithelium,indicating an abnormal immune-inflammatory response.To investigate the mechanisms by which chd8 deficiency leads to an inflammatory response in the intestines,we examined the intestines of chd8-deficient individuals and found intestinal leakage and abnormal expression of genes related to intestinal barrier functions.Treatment of chd8-deficient individuals with anti-inflammatory drugs partially alleviated intestinal inflammation,but did not improve leakage.These results suggest that chd8 deficiency may lead to intestinal barrier disruption by affecting early intestinal development,which in turn leads to an intestinal immune-inflammatory response.These findings provide clues to the management of intestinal inflammation in autism and provide an experimental basis for further studies of the gut-brain axis.