孤独症是神经发育障碍性疾病，有高遗传性，常伴发胃肠紊乱和免疫异常，但这些并发症是因是果尚不清楚。最近有报道发现母体肠源免疫分子IL-17a可进入胚胎脑影响其发育导致孤独样行为，但胚胎自身肠道是否有类似作用鲜有报道。我们初步研究发现孤独症高危基因chd8突变导致斑马鱼社交障碍和肠道紊乱等类似人的症状，胚胎肠内免疫异常激活、IL-17a等升高，而脑内小胶质细胞异常增加和激活。根据这些结果和文献报道，我们推测部分孤独症风险基因突变通过干扰胚胎肠发育而破坏肠免疫稳态，进而影响脑发育。本项目利用不受母体影响的斑马鱼，拟1）阐明chd8在肠发育和免疫稳态中的作用和机制；2）探究胚胎肠源IL-17a是否及如何影响脑发育；3）阻断IL-17a效应能否缓解或逆转脑发育和行为异常。项目的完成，将明确孤独症遗传因素在肠-免疫-脑中的作用和机制，为阐释发病机制提供新视角，为孤独症亚型的诊断和防治提供潜在靶标。

Autism is a spectrum of neurodevelopmental disorders. Autism spectrum disorders (ASD) are highly heritable and tend to be highly comorbid with other disorders, such as gastrointestinal disorders and immune dysfunction. However, it still remains mystery whether these comorbids are the cause or only the consequences of ASD. Recently it was reported that IL-17a derived from maternal gut can penetrate the fetal brain and interfere with its development. It’s not known whether fetal gut has similar effect on brain development. Our preliminary results show that the mutation of ASD high risk gene chd8 in zebrafish resulted in social disorders and gut abnormality, reminiscent of human symptoms. Futher study demonstrate that immune response in embryonic gut is abnormally exaggerated with overproduction of IL-17a, at the same time, microglia in embryonic brain is increased in number and activation. Based on these results and other reports, we propose that at least some of the ASD risk gene might cause abnormal gut development and distroy the homeostasis of gut immune system and then disturb the development of the brain. In this project, we will use zebrafish as a model organism, whose development is not affected maternally, to 1) clarify the roles played by chd8 in regulating gut development and maintaining the gut immune homeostasis and the underlying mechanisms; 2) elucidate whether and how gut-derived IL-17a participates in brain development; 3) explore whether blocking the effect of IL-17a can ameliorate or reverse the disorders of brain development and behavior. The accomplishment of the project will be helpful to understand the role and mechanisms of ASD risk genes in gut-immune-brain, will add new view to clarifying the mechanisms of ASD and will also provide potential new diagnostic and therapeutic targets.