Li Bosheng, Xiong Yiting, Li Yongming
Department of Orthodontics, Shanghai Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology, Stomatological Hospital and Dental School, Tongji University, Shanghai, China.
Psychiatry Clin Psychopharmacol. 2025 Mar 17;35(1):6-13. doi: 10.5152/pcp.2025.24966. eCollection 2025 Mar.
Autism spectrum disorder (ASD) is a complex neuropsychiatric condition with a multifactorial etiology, involving both genetic predisposition and environmental factors. Valproic acid (VPA), a commonly used antiepileptic drug, has been shown to induce ASD-like behaviors in rodent models, making it a valuable tool for studying the pathophysiology of ASD. This study aims to explore the effects of VPA on behavior and the microbiota in a mouse model of ASD.
C57BL/6 mice were used in this study, with pregnant females receiving a single intraperitoneal injection of VPA (450 mg/kg) or a saline solution on gestational day E12.5. Behavioral assessments, including the Three-Chamber Social Test, Elevated Plus Maze, Marble Burying Test, Open Field Test, and Light-Dark Box Test, were conducted on 8-week-old mice. Oral and fecal samples were collected for microbiota analysis, and gene expression profiling was performed on brain samples.
VPA-treated mice exhibited significant deficits in social interaction, anxiety-like behaviors, and repetitive actions. Microbiota analysis revealed significant shifts in the composition of both oral and fecal microbial communities in VPA-treated mice, with reductions in alpha diversity and changes in the relative abundance of specific taxa. Gene set variation analysis of mice harboring VPA-induced microbiota identified notable discrepancies in metabolic pathways, suggesting that the dysbiosis may modulate the expression of genes involved in critical metabolic processes.
The present study provides evidence that VPA exposure during early development can induce ASD-like behaviors in mice, along with significant changes in the composition of the microbiota. These findings underscore the complex interplay between environmental factors, such as VPA, and the microbiota in the pathophysiology of ASD. The study lays the groundwork for future research aimed at developing targeted interventions to mitigate the symptoms of ASD and other neuropsychiatric disorders, potentially through modulating the microbiota-gut-brain axis.
自闭症谱系障碍（ASD）是一种复杂的神经精神疾病，病因多因素，涉及遗传易感性和环境因素。丙戊酸（VPA）是一种常用的抗癫痫药物，已被证明可在啮齿动物模型中诱导出类似ASD的行为，使其成为研究ASD病理生理学的宝贵工具。本研究旨在探讨VPA对ASD小鼠模型行为和微生物群的影响。
本研究使用C57BL/6小鼠，怀孕母鼠在妊娠第12.5天接受单次腹腔注射VPA（450mg/kg）或生理盐水。对8周龄小鼠进行行为评估，包括三室社交试验、高架十字迷宫试验、埋珠试验、旷场试验和明暗箱试验。收集口腔和粪便样本进行微生物群分析，并对脑样本进行基因表达谱分析。
VPA处理的小鼠在社交互动、焦虑样行为和重复动作方面表现出明显缺陷。微生物群分析显示，VPA处理的小鼠口腔和粪便微生物群落组成发生了显著变化，α多样性降低，特定分类群的相对丰度改变。对具有VPA诱导微生物群的小鼠进行基因集变异分析，发现代谢途径存在显著差异，表明微生物群失调可能调节参与关键代谢过程的基因表达。
本研究提供了证据，表明早期发育期间暴露于VPA可在小鼠中诱导出类似ASD的行为，同时微生物群组成也发生显著变化。这些发现强调了环境因素（如VPA）与微生物群在ASD病理生理学中的复杂相互作用。该研究为未来旨在开发针对性干预措施以减轻ASD和其他神经精神疾病症状的研究奠定了基础，可能通过调节微生物群-肠道-脑轴来实现。
