Valproic Acid-Induced Autistic-Like Behavior Is Accompanied by Intestinal Damage Driving Changes in Gut Permeability
Bruna Longo1,2, Ruan Kaio Silva Nunes2, Camila André Cazarin2
1Department of Pharmacology, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil.
Journal of Neurochemistry
|December 15, 2025
Summary
Valproic acid exposure in utero alters gut barrier function and behavior, particularly in male rats, suggesting a role for intestinal dysfunction in autism spectrum disorder (ASD) and highlighting sex-specific effects.
Area of Science:
- Neuroscience
- Gastroenterology
- Developmental Biology
Background:
- Autism spectrum disorder (ASD) is often accompanied by gastrointestinal (GI) disturbances.
- These GI issues can worsen behavioral symptoms in individuals with ASD.
- Valproic acid (VPA) exposure during gestation is a known risk factor for ASD.
Purpose of the Study:
- To investigate in utero VPA exposure effects on intestinal mucosa and permeability in a rat model.
- To examine sex-specific differences in VPA-induced alterations.
- To explore potential mechanisms linking gut barrier dysfunction to ASD-like behaviors.
Main Methods:
- Rats exposed to VPA in utero were assessed for social behavior.
- Intestinal and blood-brain barrier (BBB) permeability were measured using FITC-dextran and Evans blue.
- Histological analyses, mucin quantification, inflammatory/oxidative markers, 5-HT levels, and serum LPS were analyzed.
Main Results:
- VPA-exposed males, not females, showed reduced social interaction.
- Males exhibited increased intestinal and vascular permeability, elevated serum LPS, and BBB disruption.
- Both sexes showed reduced intestinal muscular layer thickness; males had higher oxidative stress markers.
Conclusions:
- The VPA rat model effectively replicates gut barrier dysfunction relevant to ASD.
- Significant sex differences exist in VPA's impact on gut-brain axis.
- Findings support targeting intestinal barrier dysfunction for personalized ASD therapies.
