International Journal for Autism Challenges & Solution

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Vol. 2 No. 2 (2025): International Journal for Autism Challenges & Solution

A Potential Link between Gut Leakiness and Sex Differences in Autism Spectrum Disorder (ASD)

  • Hanan Farouk Aly
Submitted
November 24, 2025
Published
2025-12-27

Abstract

Background: Autism is categorized as autism spectrum disorder (ASD), characterized by recurrent behaviors and difficulties with social communication that can affect different body systems and are linked to gut microbiota dysbiosis (GM). The importance of altered GM in autistic people, the ways in which these changes could result in leaky gut, and the possible connection between sex differences and this problem are all highlighted in this paper. Main body: Research indicates that increased intestinal barrier permeability may play a significant role in the pathological changes seen in autism; it makes it easier for gut-derived endotoxins to enter the brain, where they activate the TLR4–MyD88–NF-κB signaling cascade and create an inflammatory environment. There have been differences found in the amounts of various bacterial metabolites, such as beta cresol, short-chain fatty acids, lipopolysaccharides, and bacterial toxins, in the blood and urine of children with autism. Additionally, the importance of particular proteins like zonulin, lysozyme, and calprotectin as biomarkers that can detect the leaky gut in ASD at an early stage has been shown. Bacterial metabolite leakage in these patients may be explained by disruption of the gut blood–brain barrier. As a result, a number of microbiota manipulation techniques have been developed to balance out sex differences. Male ASD sufferers are four times as likely as female ASD sufferers. Additionally, in both human and animal models of this illness, such as the maternal immune activation (MIA) mice model, the composition of GM is dependent on sex. However, very few studies have taken sex's biological impact into account when assessing how GM affects symptoms of ASD. MIA increases pro-inflammatory cytokines and chemokines in the mother, such as interleukin, IL-6, and IL-17α, which interfere with the development of the fetal brain. According to recent studies, MIA causes GM dysbiosis. This is significant because the GM, which lives in the gastrointestinal (GI) tract, contributes to the development of the immunological, neurological, and metabolic systems through the microbiota-gut-brain axis, resulting in characteristics that resemble ASD in the MIA model.Research exploring the impact of GM on ASD etiology primarily focuses on men, ignoring the recipient's and donor's sex/gender, even though biological distinctions linked to sex, GM, and leaky gut have been discovered to be correlated with each other. In the MIA model, sex-mediated gut-immune interactions were found in the few research that take into account the biological impact of sex.The limited studies that consider the biological effect of sex revealed sex-mediated gut-immune interactions in the MIA model. Conclusion: Given that many people with autism have gastrointestinal problems, this review emphasizes the possible link between ASD and GM. The involvement of altered GM in autistic people, how these changes result in leaky gut, and the possible connection between leaky gut and sex differences are all covered. Furthermore, this study offers a number of promising therapeutic therapies, including as intestinal proteins, some probiotics, and chemicals derived from bacteria, as novel approaches to reestablish a healthy GM.

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