The Protective Effects of Chlorogenic Acid in Mitigating Gut-Brain Barrier Dysfunction and Autism-Like Symptoms Caused by Early-Life Stress in Mice: A Behavioral, Histopathological, and Molecular Study.

Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental condition shaped by both genetic predispositions and environmental influences. Early-life stresses (ELS), notably maternal separation (MS), can lead to behavioral impairments similar to core ASD features. Recent research indicates that disruptions in the gut-brain axis may significantly contribute to the neuropsychiatric effects of ELS. This study investigates the role of chlorogenic acid (CGA), a plant-derived polyphenol, in a mouse model of MS-induced ASD-like behaviors. Mice subjected to MS were treated with CGA via intraperitoneal injection over 2 weeks. Behavioral assessments included the open field, passive avoidance, elevated plus maze, marble burying, and three-chamber social interaction tasks. Histologic changes were assessed using H&E staining. Alterations in antioxidant capacity and gene expression were assessed in hippocampal and colonic samples using the FRAP method and qRT-PCR, respectively. CGA administration led to marked improvements in behavioral functions, such as enhanced memory, increased social engagement, and reductions in repetitive, depression, and anxiety-like behaviors. At the molecular level, CGA treatment was associated with lower hippocampal oxidative stress, elevated antioxidant capacity, decreased levels of hippocampal inflammatory markers, alongside beneficial histological changes in hippocampus and colon samples. Furthermore, CGA modulated the expression of tight junction proteins like Claudins (CLDN1, CLDN5, and CLDN12) in the colon and hippocampus, suggesting a protective effect on gut and brain barrier integrity. In summary, MS disrupts the neuro-immune balance and behavior by affecting the gut-brain axis. CGA shows promise in restoring these systems, highlighting its potential as a complementary intervention for conditions related to ASD.