Non-gene-edited neural stem cells reverse neuroinflammation and microbiota dysbiosis in a sprague-dawley rat model of autism spectrum disorder

Apr 1, 2026Translational psychiatry

Untreated neural stem cells reduce brain inflammation and gut imbalance in a rat model of autism

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Abstract

Treatment with human chemically induced pluripotent stem cell-derived neural stem cells significantly improved sociability and reduced repetitive behaviors in a rat model of autism spectrum disorder.

Increased stranger interaction time indicates improved sociability (P < 0.0001).
Decreased marble-burying behavior reflects reduced repetitive actions (P < 0.0001).
Shorter escape latency in the Morris water maze suggests enhanced spatial memory (P < 0.01).
Treatment reduced neuroinflammation by suppressing pro-inflammatory markers and elevating an anti-inflammatory marker (all P < 0.0001).
Oxidative stress markers showed improvement, with a restoration of protective antioxidants and a decrease in harmful substances.
Gut microbiota analysis revealed a balanced microbiome, with reduced harmful taxa and increased beneficial bacteria.

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Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with limited treatment options, where neuroinflammation and gut microbiota dysbiosis are emerging as interconnected therapeutic targets. This study evaluated the therapeutic potential of non-gene-edited human chemically induced pluripotent stem cell-derived neural stem cells (hCiPSC-NSCs) in a prenatal valproic acid (VPA)-induced rat model of ASD, using a dual-pathway administration strategy (intravenous systemic delivery combined with an intracerebroventricular boost). The treatment significantly ameliorated core ASD-like behaviors, including improved sociability (increased stranger interaction time, P < 0.0001), reduced repetitive behaviors (decreased marble-burying, P < 0.0001; and self-grooming, P < 0.05), and enhanced spatial memory (shorter escape latency in the Morris water maze, P < 0.01). At the mechanistic level, hCiPSC-NSCs attenuated neuroinflammation (suppressed IL-1β, IL-6, and TNF-α; elevated IL-10, all P < 0.0001), reduced oxidative stress (restored GSH and SOD, decreased MDA and NO), diminished microglial activation in the hippocampus and cortex, and restored synaptic ultrastructure by replenishing synaptic vesicles. Furthermore, 16S rRNA sequencing revealed a rebalancing of the gut microbiota, characterized by a reduced Firmicutes/Bacteroidota ratio, enrichment of beneficial taxa like Bacteroidota and Alloprevotella, suppression of pathobionts such as Desulfovibrionales, and partial restoration of microbial diversity. These findings demonstrate that non-gene-edited hCiPSC-NSCs can simultaneously address neural pathophysiology and gut ecosystem disruption in ASD, highlighting their potential as a gut-brain axis-targeting therapy for neurodevelopmental disorders.

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Non-gene-edited neural stem cells reverse neuroinflammation and microbiota dysbiosis in a sprague-dawley rat model of autism spectrum disorder

Abstract

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