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

Background: Autism is classified as autism spectrum disorder (ASD) and is marked by frequent behaviors and challenges in social communications, which can impact various bodily systems and is associated with dysbiosis of gut microbgiota (GM). This review highlights the significance of altered GM in individuals with autism, the mechanisms by which these changes may lead to leaky gut, and the potential link between sex differences and this issue. Main body: Evidence suggests that increased permeability of the intestinal barrier may be a crucial contributor to the pathological alterations detected in autism; it facilitates the transfer of gut-derived endotoxins into the brain, thereby creating an inflammatory environment by activating the TLR4–MyD88–NF-κB signaling cascade. Variations in the levels of different bacterial metabolites in the urine and blood of children with autism, including lipopolysaccharides, short-chain fatty acids, bacterial toxins and beta cresol have been identified. Furthermore, the significance of specific proteins such as zonulin, lysozyme and calprotectin has been documented as biomarkers that can early identify the leaky gut in ASD. Disruption of the gut blood–brain barrier can elucidate the leakage of bacterial metabolites in these patients. Consequently, several microbiota manipulation strategies have been devised to restore their balance concerning sex differences. ASD affected males are 4 times ASD affected females. Also, the composition of GM depends on the sex both in human and in animal models of this disorder involving the maternal immune activation (MIA) mouse model. Nevertheless, only few investigations have considered the biological effect of sex when evaluating the influence of GM on ASD symptoms. MIA elevates maternal pro-inflammatory cytokines and chemokines, including interleukin IL-6 and IL-17α, which disrupt fetal brain growth. Recent research has indicated that MIA results in GM dysbiosis. This has great importance because the GM, which resides in the gastrointestinal (GI) tract, plays a role in the development of the metabolic, immune, and nervous systems through the microbiota-gut-brain axis leading to traits similar to ASD found in the MIA model. While the biological differences related to sex, GM and leaky gut have been found to be associated with each other research examining the influence of GM on ASD pathogenesis predominantly focuses on males neglecting the recipients and donors sex/gender. The limited studies that consider the biological effect of sex revealed sex-mediated gut-immune interactions in the MIA model. Conclusion: This review highlights the likely connection between ASD and GM, as many individuals with autism experience gastrointestinal issues. It discusses the involvement of altered GM in autistic individuals, how these alterations lead to leaky gut and the potential relationship between leaky gut and sex differences. Additionally, this review presents various therapeutic interventions with potential, including specific probiotics, intestinal proteins, and compounds derived from bacteria, as new possible strategies to restore a healthy GM.