Integrative multi-omics reveals microbial genomic variants driving altered host-microbe interactions in autism spectrum disorder

Emerging evidence links the gut microbiome to autism spectrum disorder (ASD), yet the role of microbial genomic variation remains underexplored. We generated a large-scale metagenomic and metabolomic dataset from over 1,100 children, integrating public datasets, to characterize ASD-associated microbial changes. We identified 35 species, 213 genes, 28 pathways, and 99 metabolites, alongside 1,369 single-nucleotide variants, 233 insertions/deletions, and 195 structural variants with differential abundance. Profiling of microbial genomic variation revealed 33 species and 196 enzymes lacking abundance differences, yet exhibiting significant sequence variation. Integrated analysis of microbial variants and metabolites uncovered 357 neurological associations, with mediation analysis showing that several metabolites link microbial variants to the ASD phenotype. Importantly, diagnostic models incorporating microbial variant and/or metabolite features achieved superior performance and generalizability. Our findings highlight microbial genomic variation as a critical, previously overlooked dimension of ASD-associated dysbiosis, offering valuable insights for diagnosis and mechanistic studies.