Melatonin Improves Intestinal Barrier Impairment in a Mouse Model of Autism Spectrum Disorder

TL;DR

Melatonin improves gut barrier function in a mouse model of autism, potentially reducing gastrointestinal issues commonly seen in autism spectrum disorder.

Contribution

This study demonstrates that melatonin can improve intestinal barrier integrity in an autism mouse model through modulation of tight junction proteins.

Findings

Melatonin treatment normalized intestinal villus height and crypt depth in ASD model mice.

Melatonin reduced gut inflammation and improved tight junction protein expression in the ileum.

Oral melatonin improved gut barrier integrity, potentially reducing leaky gut in autism.

Abstract

Many individuals with autism spectrum disorder experience not only challenges with social interaction and behavior but also gastrointestinal problems such as dysbiosis and increased gut permeability. These issues may be linked to changes in the gut barrier, which normally acts to restrict the passage of ions, molecules, and cells through the paracellular space. In this study, we explored whether melatonin, an endogenous biomolecule often used in sleep disorders, could also help improve gut health in a well-established mouse model of autism. Mice with autism-like traits showed altered intestinal villi, signs of gut inflammation, and impaired gut barrier function. After being treated with melatonin every day for 16 weeks, these mice showed improvements in gut structure and reduced inflammation. Most importantly, the integrity of the gut barrier improved, likely due to the modulation of key proteins that control its function, which may help prevent harmful substances from entering the body. These results suggest that melatonin could improve gut barrier integrity and overall well-being, offering a new perspective on managing autism-related comorbidities.

Autism spectrum disorder (ASD) is a neurodevelopmental condition mainly characterized by social impairments and repetitive behaviors. An altered intestinal barrier morphology and increased transmucosal leaks have also been implicated in ASD; in fact, comorbidities such as gastrointestinal problems (leaky gut) have frequently been reported in these patients. The regulation of tight junctions (TJs) is essential in maintaining intestinal barrier morphology and in regulating the delicate balance of trafficking between the intestinal lumen and the submucosa. To date, there are no definitive treatments for ASD comorbidities; however, melatonin (MLT) represents a well-validated and tolerated treatment for sleep disorders in ASD patients. The potential beneficial effects of MLT on this disorder have been and continue to be better investigated. In this context, the present study examines the effects of oral MLT administration (10 mg/kg/day for 16 weeks) on the intestinal barrier in BTBR T + Itpr3tf/J (BTBR) mice, a validated ASD model. Morphological analyses of the ileum of these animals reveal modified villus height (Vh), crypt depth (Cd), and Vh–Cd ratios; an inflammatory state; and a decrease in Paneth cells. Moreover, these mice showed altered TJ expression compared to the control animals (C57BL6/J mice). Notably, MLT normalizes morphological indices and TJ expression, consistent with an improved gut barrier morphology. These data collectively suggest that orally administered MLT can promote the remodeling of the intestinal barrier; thus, we can suppose that MLT reduces gastrointestinal barrier leaks. The overall safety and economy of MLT use suggest that this indolamine could be efficacious as an adjuvant therapy to reduce the condition known as leaky gut.

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