The gut microbiota regulates autism-like behavior by mediating vitamin B6 homeostasis in EphB6-deficient mice
The gut microbiota regulates autism-like behavior by mediating vitamin B6 homeostasis in EphB6-deficient mice
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EphB6 缺陷小鼠的肠道微生物群通过介导维生素 B-6 稳态来调节自闭症样行为
DOI：
10.1186/s40168-020-00884-z
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发表时间：
2020-08-20
期刊：
影响因子：
15.5
通讯作者：
Li, Jian-Ming
中科院分区：
文献类型：
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作者：
Li, Ying;Luo, Zheng-Yi;Li, Jian-Ming
背景资料：自闭症谱系障碍（ASD）是一种发育障碍，目前针对自闭症核心症状的有效药物治疗方法有限。越来越多的证据，特别是来自ASD患者的临床研究，表明肠道微生物群与ASD的发展之间存在功能性联系。然而，ASD中肠道微生物群与脑功能障碍（肠-脑轴）之间的联系机制尚未完全阐明。由于其在ASD患者中的基因突变和表达下调，EPHB 6也在肠道稳态中起重要作用，通常被认为是ASD的候选基因。然而，EPHB 6在调节肠道菌群和ASD发生发展中的作用和机制尚不清楚。更重要的是，从EphB 6缺陷型小鼠的粪便微生物群的移植导致在自闭症治疗的C57 BL/6 J小鼠中的自闭症样行为，并且从野生型小鼠的粪便微生物群的移植改善了EphB 6缺陷型小鼠中的自闭症样行为。在代谢水平上，EphB 6缺陷小鼠的肠道微生物群紊乱导致维生素B（6）和多巴胺缺陷。在细胞水平上，EphB 6缺陷小鼠的内侧前额叶皮层的兴奋/抑制（E/I）平衡由肠道微生物群介导的维生素B（6）调节。我们的研究揭示了肠道微生物群在EphB 6缺陷小鼠中通过维生素B-6、多巴胺和E/I平衡调节自闭症样社会行为中的关键作用，这些发现为理解和治疗ASD提供了新的策略。
Background: 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 ofEPHB6in regulating the gut microbiota and the development of ASD are unclear.Results: 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 B(6)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 B(6)in EphB6-deficient mice.Conclusions: Our study uncovers a key role for the gut microbiota in the regulation of autism-like social behavior by vitamin B-6, dopamine, and the E/I balance in EphB6-deficient mice, and these findings suggest new strategies for understanding and treating ASD.