Sex-Specific Gut Microbiota-Metabolite Interactions in Autism Spectrum Disorder: Dysbiosis, Metabolic Disruptions, and Niche Competition Dynamics

Background: Autism Spectrum Disorder (ASD), a neurodevelopmental disorder, is marked by impaired social interaction, communication difficulties, and repetitive behaviors. Gut microbiota influences host metabolism and behavior via the microbiota-gut-brain axis, yet how gut microbial dysbiosis contributes to ASD is unclear. This study aimed to identify potential microbial and metabolic markers for an ASD predictive diagnostic model using gut microbiome data. Results: Analysis of 16S rRNA sequencing data from the GMrepo v2 database showed significant differences (LDAscore > 0) in gut microbiota abundance in ASD individuals at genus levels (e.g., Pseudomonas, Pseudoflavonifractor, Enterococcus). These microbes may be involved in immune regulation, etc. Metabolic flux analysis identified metabolites like L-methionine (p < 0.01) associated with ASD, participating in antioxidant defense. Mediation analysis supported a “microbiota-metabolite-disease” pathway (Pmedi < 0.001). Sex-based stratification revealed more pronounced alterations in males with ASD. Over 90% of microbial species showed stronger metabolic competition. Conclusions : This study elucidates a complex gut microbiota-host metabolism interaction network in ASD, identifying markers with mechanistic and diagnostic value. Emphasizing sex’s importance, it proposes altered niche competition may affect community stability, offering new insights into ASD’s microbial mechanisms and a foundation for gut microbiota-targeted interventions.