Autism spectrum disorder (ASD) is a developmental disorder, and the effective pharmacological treatments for the core autistic symptoms are currently limited. Increasing evidence, particularly that from clinical studies on ASD patients, suggests a functional link between the gut microbiota and the development of ASD. However, the mechanisms linking the gut microbiota with brain dysfunctions (gut-brain axis) in ASD have not yet been full elucidated. Due to its genetic mutations and downregulated expression in patients with ASD, EPHB6, which also plays important roles in gut homeostasis, is generally considered a candidate gene for ASD. Nonetheless, the role and mechanism of EPHB6 in regulating the gut microbiota and the development of ASD are unclear. Here, we found that the deletion of EphB6 induced autism-like behavior and disturbed the gut microbiota in mice. More importantly, transplantation of the fecal microbiota from EphB6-deficient mice resulted in autism-like behavior in antibiotic-treated C57BL/6J mice, and transplantation of the fecal microbiota from wild-type mice ameliorated the autism-like behavior in EphB6-deficient mice. At the metabolic level, the disturbed gut microbiota in EphB6-deficient mice led to vitamin B6 and dopamine defects. At the cellular level, the excitation/inhibition (E/I) balance in the medial prefrontal cortex was regulated by gut microbiota-mediated vitamin B6 in EphB6-deficient mice. Our study uncovers a key role for the gut microbiota in the regulation of autism-like social behavior by vitamin B6, dopamine, and the E/I balance in EphB6-deficient mice, and these findings suggest new strategies for understanding and treating ASD.

中文翻译：

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肠道菌群通过介导EphB6缺陷小鼠中的维生素B6稳态来调节自闭症样行为。

自闭症谱系障碍（ASD）是一种发育障碍，目前对核心自闭症症状的有效药理治疗受到限制。越来越多的证据，特别是来自对ASD患者的临床研究的证据表明，肠道菌群与ASD的发展之间存在功能联系。然而，尚不完全阐明将肠道菌群与ASD中脑功能障碍（肠脑轴）联系起来的机制。由于其基因突变和在ASD患者中的表达下调，EPHB6在肠道稳态中也起着重要作用，通常被认为是ASD的候选基因。然而，尚不清楚EPHB6在调节肠道菌群和ASD发生中的作用和机制。这里，我们发现EphB6的缺失会诱发自闭症样行为并扰乱小鼠的肠道菌群。更重要的是，从EphB6缺陷小鼠移植粪便菌群会导致抗生素治疗的C57BL / 6J小鼠出现自闭症样行为，而从野生型小鼠的粪便微生物菌群移植会缓解EphB6缺陷小鼠的自闭症样行为。 。在代谢水平上，EphB6缺陷小鼠的肠道微生物区系受到干扰，导致维生素B6和多巴胺缺陷。在细胞水平，内侧前额叶皮层中的兴奋/抑制（E / I）平衡受肠道菌群介导的EphB6缺陷小鼠维生素B6的调节。我们的研究揭示了肠道微生物群在EphB6缺陷小鼠中通过维生素B6，多巴胺和E / I平衡调节自闭症样社会行为的关键作用，