EphB6通过肠-脑-微生物轴参与自闭症的效应及其调控机制

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder in children. However, the mechanism of ASD is still not well-characterized. Our pre-experiments found that EphB6 knockout mice displayed autism-like behaviors. Meanwhile, EphB6 knockout mice showed gut dysbacteriosis. Importantly, transplantation of fecal microbiota of EphB6 knockout mice could induce autism-like behaviors in C57BL/6J mice. Also, transplantation of fecal microbiota of wild type mice, which ameliorated gut dysbacteriosis in EphB6 knockout mice, ameliorated the social defects and repetitive behavior of EphB6 knockout mice. Functionally, we found genomic abundance of vitamin B6 metabolism pathway was decreased in fecal microbiota of EphB6 knockout mice. Also, the level of vitamin B6 was decreased in plasma and PFC of EphB6 knockout mice. By injecting vitamin B6 intraperitoneally, EphB6 knockout mice showed an improvement in social behavior. Based on these results, we hypothesized EphB6 modulated autism-like behaviors of mice by gut microbiota, probably by regulating vitamin B6 metabolism. We proposed to prove the role and regulatory mechanism of EphB6 on autism-like behaviors by gut microbiota in mice by using various mouse models. This project will uncover new mechanisms of ASD and provide potential new therapies to treat ASD patients.

自闭症谱系障碍（Autism spectrum disorder，ASD）是儿童常见的神经发育障碍性疾病，其发病机制尚不明确。前期我们发现EphB6基因敲除小鼠出现自闭症样行为，同时伴有肠道菌群的紊乱。重要的是，移植EphB6基因敲除小鼠肠道微生物可使C57BL/6J小鼠表现出自闭症样行为，而移植野生型小鼠肠道微生物可改善EphB6基因敲除小鼠的自闭症样行为。功能上EphB6基因敲除小鼠肠道微生物中参与维生素B6代谢通路的基因丰度下降，小鼠血浆和前额叶皮层中维生素B6相对含量下降，而给EphB6基因敲除小鼠补充维生素B6可以改善小鼠受损的社交行为。基于此，我们提出EphB6通过肠道微生物调节维生素B6代谢从而参与小鼠自闭症样行为。本项目拟采用多种小鼠模型明确EphB6通过肠道微生物参与小鼠自闭症样行为的作用及机制。本项目将揭示ASD发生的新机制，并为ASD患者治疗提供潜在的新策略。

自闭症谱系障碍(Autism spectrum disorder, ASD)是发育障碍性疾病。目前，用于治疗ASD核心症状的药物比较有限。大量临床研究提示，肠道菌群与ASD的发展存在相关性。但是，肠道菌群的改变导致ASD患者大脑功能异常的机制还需要进一步探索。Eph受体家族基因在肠上皮稳态中发挥重要作用。近年来，EPHB6被广泛地认为是ASD相关基因，且在ASD患者脑组织中下调。 然而，EPHB6在调节肠道菌群及参与ASD中的作用及机制尚不清楚。使用行为学实验、16S rRNA扩增子测序、代谢组分析及电生理实验，我们发现EphB6基因敲除小鼠表现出自闭症样行为及肠道菌群的改变。EphB6基因敲除小鼠中肠道菌群可诱使C57BL/6J小鼠出现肠道菌群的改变及自闭症样行为。而且，野生型小鼠中肠道菌群可改善EphB6基因敲除小鼠的自闭症样行为。代谢水平上，EphB6基因敲除小鼠中肠道菌群的改变降低了血浆中的维生素B6及前额叶皮层中的多巴胺。细胞水平上，EphB6基因敲除小鼠中肠道菌群的改变引起了前额叶皮层中兴奋/抑制失平衡，且可被多巴胺D1受体激动剂改善。综上所述，我们的研究证实了EphB6通过肠道菌群调节维生素B6、多巴胺及兴奋/抑制平衡参与自闭症样行为的作用，提示了用于治疗ASD患者的新策略。