ORIGINAL RESEARCH article
Front. Immunol.
Sec. Microbial Immunology
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1680179
This article is part of the Research TopicThe Gut-Brain Axis: Microbiota-Driven Immune Modulation and its Impact on Neurological HealthView all 9 articles
3KO-NSCs Ameliorate Behavioral Deficits and Modulate Gut Microbiota in a VPA-Induced C57BL/6 Mouse Model of Autism
Provisionally accepted
- 1Guangdong Academy of Sciences Institute of Biological and Medical Engineering, Guangzhou, China
- 2Guangzhou Health Science College, Guangzhou, China
- 3Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences (CAS), Guangzhou, China
- 4Chinese Academy of Sciences Guangzhou Institutes of Biomedicine and Health, Guangzhou, China
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Background: Autism spectrum disorder (ASD) involves complex neurological and gastrointestinal pathophysiology. Existing therapies rarely address the gut-brain axis connection. This study evaluated the therapeutic potential of immune-evasive human induced pluripotent stem cell-derived neural stem cells (3KO-NSCs) in a mouse model of ASD. Methods: We used a valproic acid (VPA)-induced ASD model in C57BL/6 mice. Mice received systemic administration of 3KO-NSCs. Assessments included behavioral assays (social interaction, repetitive behaviors), hippocampal cytokine profiling (IL-6, TNF-α), 16S rRNA sequencing for gut microbiota analysis, immunohistochemistry (Iba1+ microglia), and ultrastructural synaptic analysis. Results: 3KO-hiPSC-NSC treatment significantly ameliorated VPA-induced ASD-like behaviors. It reduced hippocampal neuroinflammation (decreased IL-6 and TNF-α) and attenuated microglial overactivation (reduced Iba1+ cells), correcting synaptic pruning abnormalities. Concurrently, treatment restored gut microbiota diversity (increased Shannon index), enriching Bacteroides and reducing pro-inflammatory Proteobacteria. Conclusions: 3KO-NSCs exert dual therapeutic effects by mitigating central neuroinflammation and rebalancing gut microbiota. This provides the first direct evidence that stem cell therapy can modulate the gut-brain axis to treat ASD, positioning 3KO-NSCs as a novel bifunctional therapeutic strategy.
Keywords: 3KO-NSCs, Autism spectrum disorder (ASD), VPA, Neuroinflammation, Microbiota dysbiosis
Received: 05 Aug 2025; Accepted: 10 Sep 2025.
Copyright: © 2025 Wu, Li, Wang, Yang and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Caixia Wu, caixia52@163.com
Zhaoming Liu, liu_zhaoming@gibh.ac.cn
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.