Integrated multi-omics analysis reveals the involvement of the gut-brain axis in children with autism.

Background: Autism Spectrum Disorder (ASD) is frequently accompanied by gastrointestinal (GI) comorbidities and gut microbiota dysbiosis. While the microbiota-gut-brain axis is implicated in ASD pathophysiology, the upstream host genetic factors that drive these specific microbial alterations remain poorly characterized. Methods: To bridge this gap, we performed an integrated multi-omics analysis combining whole-exome sequencing, 16S rRNA gene sequencing, and plasma metabolomics in a cohort of children with ASD and typically developing controls. Results: We confirmed that children with ASD exhibit significant gut microbial dysbiosis and metabolic perturbations, which correlated with GI symptom severity. Crucially, rare variant enrichment analysis identified a significant accumulation of deleterious variants in mucin biosynthesis pathways (specifically the MUC gene family), which are essential for intestinal mucus barrier integrity. Multi-omics integration revealed that these host genetic defects were associated with distinct shifts in the gut ecosystem, notably the depletion of beneficial butyrate-producing bacteria (e.g., Faecalibacterium) and the expansion of mucin-degrading taxa. This structural dysbiosis translated into functional metabolic impairments, particularly in lipid transport and short-chain fatty acid metabolism, which tracked with ASD severity. Conclusion: Collectively, our data argue for a host-centric cascade where genetic vulnerabilities-specifically within the MUC pathway-compromise mucosal integrity, acting as a selective filter that fundamentally reshapes the gut microbiome. By pinpointing these variants as upstream drivers of gut-brain axis dysfunction, we move beyond simple association to identify concrete genetic targets-rare deleterious variants in the mucin (MUC) gene family-for future precision interventions in ASD.