Community Modeling Reveals Disrupted Gut Microbial Secretion in Autism Associated With Redox and Neurometabolic Alterations

Emerging evidence suggests that disruptions in the gut microbiome may influence autism spectrum disorder (ASD) through altered microbial metabolism and gut-brain communication. However, the specific metabolic impacts of these microbial changes remain unclear. Community-scale metabolic modeling was applied to shotgun metagenomics data from children with ASD and neurotypical controls to predict secretion of host-impacting metabolites. Modeled ASD-associated communities exhibited altered predicted secretion of metabolites related to redox balance and neurotransmission, including increased 2-ketobutyrate and GABA and reduced riboflavin and inositol, with microbiota transfer therapy (MTT) shifting these profiles toward NT. Empirical fecal metabolomics data showed generally consistent directional trends with model predictions. Reductions in autism severity scores following MTT were associated with increased predicted secretion potentials for inositol and arginine. Taxonomic analysis revealed a depletion of beneficial and an enrichment of pro-inflammatory species, such as Escherichia and Flavonifractor, in ASD. Associations between microbial taxa (e.g., Bacteroides, Bifidobacterium) and neuroactive metabolites highlight microbial modulation as a promising therapeutic strategy in ASD. These results emphasize microbial metabolism as a contributor to ASD traits and a target for therapeutic intervention.