Large-scale metagenomic analysis of oral microbiomes reveals markers for autism spectrum disorders Original paper

What was studied?

The study examined oral microbiome autism markers using large-scale, deep metagenomic sequencing of saliva to determine how microbial community structure differs between children with autism spectrum disorder (ASD) and their neurotypical siblings. Leveraging more than 7000 whole-genome sequenced salivary metagenomes, the researchers aimed to identify species-level signatures, ecological shifts, and microbial functions that characterize ASD. Core objective: using high-resolution metagenomics to clarify whether reproducible, clinically meaningful microbial markers exist in the oral cavity that can discriminate ASD status and potentially relate to cognitive impairment, diet, or behavioral traits such as mouth-breathing.

Who was studied?

The cohort included 2154 children with ASD and 1646 neurotypical (NT) siblings, making it one of the largest oral metagenomic ASD datasets to date. The sample included paired family members, allowing for the analysis of microbiome strain sharing between children and their parents. The population was primarily composed of salivary samples collected across diverse households, providing environmental and genetic heterogeneity. According to demographic summaries in early pages of the paper, the study design emphasized sibling-matched controls to minimize confounding from diet, environment, and early-life exposures—variables known to influence the oral microbiome.

Most important findings

Across the dataset, researchers identified 108 species that significantly differentiated ASD from NT siblings (q <0.005). Many ASD-associated taxa were aerobic or aerotolerant species, including Rothia dentocariosa, Streptococcus gordonii, Cutibacterium acnes, and Corynebacterium durum. As visualized in figures on pages 3–5, NT-associated species were predominantly anaerobes, suggesting an ecological shift toward oxygen-tolerant organisms in ASD. This pattern was linked to increased mouth-breathing, a common behavioral trait in ASD that may elevate oral oxygen exposure and alter niche conditions. Microbial load had only a limited influence on case–control differences. Although some ASD-linked species were also associated with higher microbial load, the majority of taxa remained significant after controlling for inferred oral hygiene. Functional analysis revealed that pathways associated with oxidative stress tolerance, carbohydrate metabolism, and biofilm formation were enriched in ASD samples. Species-level correlations showed strong associations between microbial signatures and cognitive impairment, with several ASD-enriched species displaying positive correlations with lower IQ scores.

Strain-sharing analyses indicated that ASD children exhibited reduced sharing of oral microbial strains with parents, suggesting altered microbial transmission dynamics or stronger host-driven ecological filtering. Machine-learning classifiers achieved an AUC of 0.66 for ASD discrimination—modest but notable given the complexity of ASD biology.

Key implications

The work demonstrates that the oral microbiome contains reproducible microbial features associated with ASD, independent of hygiene-related microbial load. The pronounced increase in aerotolerant species points to behavioral-environmental interactions, particularly mouth-breathing, as a potential ecological driver. These findings refine the growing microbial signature landscape for ASD and offer clinically relevant insights for biomarker development, early-life screening, and exploration of oral–brain communication pathways. They also reinforce the value of the oral microbiome as a noninvasive biospecimen that may complement gut-focused ASD research.

Citation

Manghi P, Filosi M, Zolfo M, et al. Large-scale metagenomic analysis of oral microbiomes reveals markers for autism spectrum disorders. Nature Communications. 2024;15:9743. doi:10.1038/s41467-024-53934-7