Valproic Acid-Induced Autistic-Like Behavior Is Accompanied by Intestinal Damage Driving Changes in Gut Permeability in a Sex-Dependent Way in Rats.

A significant proportion of individuals with autism spectrum disorder (ASD) experience gastrointestinal disturbances exacerbating behavioral symptoms. Therefore, this study investigated alterations in the intestinal mucosa that influence intestinal permeability in rats exposed to valproic acid (VPA) in utero, as well as the sexual differences in it. After assessing social behavior, intestinal permeability was assessed using FITC-dextran, and vascular permeability was evaluated through Evans blue dye tests in the intestine and blood-brain barrier (BBB) of male and female offspring. Furthermore, microscopic analyses were performed to assess mucosal architecture and quantify mucin levels, while inflammatory and oxidative parameters, 5-HT and 5-HIAA levels, and serum lipopolysaccharide (LPS) concentrations were measured. Males, but not females, exposed to VPA exhibited reduced social interaction time. Only VPA males showed increased intestinal and vascular permeability, histological changes, elevated mucin levels, and higher serum LPS levels. Male, but not female, rats exposed to VPA displayed increased BBB permeability, and both showed reduced intestinal muscular layer thickness. Additionally, males showed increased levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and enhanced glutathione S-transferase (GST) and myeloperoxidase (MPO) activities. Conversely, females exhibited no elevation in ROS or MDA intestinal levels. Moreover, a reduction in 5-HT turnover was evidenced in VPA-females compared to VPA-males. These findings support the validity of this model as a tool for investigating the role of intestinal barrier dysfunction in ASD and for identifying novel pharmacological targets in this field, considering the sexual differences in search of the practice of personalized and precision medicine.