Title : Gut-brain axis in autism spectrum disorder: MicroRNAs as a critical mediator of pathogenesis
Abstract:
Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by persistent impairments in social communication and the presence of restricted, repetitive patterns of behavior. Although the etiology of ASD remains incompletely understood, accumulating evidence implicates the gut–brain axis as a significant pathway in its pathogenesis, with gut microbial dysbiosis emerging as a consistent finding in affected individuals. However, the precise molecular mechanisms bridging gut microbiota alterations and central nervous system dysfunction have yet to be fully elucidated. This review critically synthesizes current evidence to propose a mechanistic framework in which microRNAs (miRNAs)—small, non-coding RNA molecules that function as epigenetic regulators of gene expression—serve as pivotal mediators linking gut microbial dysbiosis to neuroinflammation and subsequent ASD pathophysiology. Emerging data indicate that specific miRNAs, particularly miR-146a and miR-155, are dysregulated in the brains and peripheral circulation of individuals with ASD, and their expression patterns are significantly influenced by the composition of the gut microbiota. Mechanistically, gut-derived microbial products, such as lipopolysaccharides and other inflammatory stimuli, can activate the nuclear factor kappa-B (NF-κB) signaling cascade, which in turn upregulates miR-146a and miR-155 expression. These miRNAs then propagate neuroinflammatory signals through the modulation of innate immune responses, contributing to chronic central nervous system inflammation, altered neuronal development, and synaptic dysfunction. Additional miRNAs, including miR-181, have also been implicated in ASD pathogenesis, with evidence suggesting their involvement in immune regulation and the expression of ASD-related genes such as neurexin 1. Furthermore, the review highlights that probiotic interventions capable of restoring gut microbial balance have been shown to modulate miRNA expression, thereby attenuating inflammatory cascades and ameliorating behavioral symptoms in preclinical models. In conclusion, the evidence supports a model in which miRNA-mediated neuroinflammation, driven by gut microbial dysbiosis, constitutes a critical mechanistic link in the pathogenesis of ASD. This emerging paradigm not only deepens our understanding of the gut–brain axis in neurodevelopmental disorders but also identifies miRNAs as promising diagnostic biomarkers and potential therapeutic targets for novel intervention strategies in ASD.
