Melatonin's effects on microbiota-gut-brain axis in autism spectrum disorder mice

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by social impairments and repetitive behaviors, with an unclear etiology. Growing evidence has highlighted alterations in gut microbiota and dysfunctions in the intestinal barrier in ASD patients, leading to the pathological phenomenon of "leaky gut". This condition may be linked to impairments in the blood-brain barrier, which could additionally affect brain development and behavior. In this context, the concept of the microbiota-gut-brain axis has gained increasing attention, highlighting the interplay between the gut microbiota and the central nervous system. The present study aimed to explore the mechanisms underlying intestinal barrier dysfunction in the BTBR T+Itpr3tf/J mouse model of ASD, focusing on the effects of melatonin treatment. Melatonin, known for its role in regulating circadian rhythms, also possesses well-documented anti-inflammatory and antioxidant properties. The goal was to investigate how melatonin could influence intestinal morphology and the expression of tight junction proteins (such as zonulin-1, claudin-1, and claudin-2), which are essential for regulating intestinal permeability. Morphological analyses were performed to assess potential alterations in intestinal villus architecture and the intestinal epithelium, while immunohistochemical and biochemical analyses were used to evaluate the expression of tight junction proteins. The ASD mice exhibited longer intestinal villi and changes in the epithelial surface compared to control animals (C57BL6J mice), which could increase intestinal permeability and alter gut microbiota composition. The melatonin-treated ASD mice showed a reduction in intestinal permeability, linked to the modulation of the expression of key tight junction proteins. These findings support the involvement of the microbiota-gut-brain axis in ASD pathology and suggest that melatonin may provide a potential therapeutic strategy to alleviate some ASD symptoms and comorbidities.