Abstract
The link between the oral microbiome and neurodevelopmental disorders remains a compelling hypothesis, still requiring confirmation in large-scale datasets. Leveraging over 7000 whole-genome sequenced salivary samples from 2025 US families with children diagnosed with autism spectrum disorders (ASD), our cross-sectional study shows that the oral microbiome composition can discriminate ASD subjects from neurotypical siblings (NTs, AUC = 0.66), with 108 differentiating species (q < 0.005). The relative abundance of these species is highly correlated with cognitive impairment as measured by Full-Scale Intelligence Quotient (IQ). ASD children with IQ < 70 also exhibit lower microbiome strain sharing with parents (p < 10-6) with respect to NTs. A two-pronged functional enrichment analysis suggests the contribution of enzymes from the serotonin, GABA, and dopamine degradation pathways to the distinct microbial community compositions observed between ASD and NT samples. Although measures of restrictive eating diet and proxies of oral hygiene show relatively minor effects on the microbiome composition, the observed associations with ASD and IQ may still represent unaccounted-for underlying differences in lifestyle among groups. While causal relationships could not be established, our study provides substantial support to the investigation of oral microbiome biomarkers in ASD.