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

## TL;DR

This study finds that changes in gut microbes' DNA and their byproducts are linked to autism, offering a new way to diagnose and understand the condition.

## Contribution

The study reveals microbial genomic variants as a new dimension of gut dysbiosis in autism, beyond abundance-based analysis.

## Key findings

- Microbial genomic variants and metabolites are linked to autism through altered host-microbe interactions.
- A 20-marker multi-omics panel enables accurate, non-invasive ASD diagnosis.
- 357 neurological associations were found between microbial variants and metabolites in autism.

## Abstract

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.

•Large-scale metagenomic and metabolomic integration across >1,100 children with ASD•Microbial genomic variants define a distinct layer of ASD-associated dysbiosis•Variant-driven metabolic alterations link microbial genetics to ASD pathophysiology•A 20-marker multi-omics panel enables accurate, non-invasive ASD diagnosis

Large-scale metagenomic and metabolomic integration across >1,100 children with ASD

Microbial genomic variants define a distinct layer of ASD-associated dysbiosis

Variant-driven metabolic alterations link microbial genetics to ASD pathophysiology

A 20-marker multi-omics panel enables accurate, non-invasive ASD diagnosis

Integrating gut metagenomic and metabolomic profiles from over 1,100 children, Chen et al. identify microbial genomic variants and metabolic shifts associated with autism spectrum disorder, providing a multi-layered signature for precise, non-invasive diagnosis and mechanistic understanding.