Systemic Uremic Toxin Burden in Autism Spectrum Disorder: A Stratified Urinary Metabolite Analysis

Area of Science:

• Microbiology
• Metabolomics
• Neurodevelopmental Disorders

Background:

• Autism spectrum disorder (ASD) is increasingly linked to gut microbial and metabolic disturbances.
• Altered production of gut-derived uremic toxins is a key feature of these metabolic changes.

Purpose of the Study:

• To investigate urinary concentrations and functional ratios of five key uremic toxins in children with ASD compared to healthy controls.
• To explore how these toxin profiles differ based on sex, age, and autism severity.

Main Methods:

• Measured urinary indoxyl sulfate (IS), p-cresyl sulfate (PCS), trimethylamine N-oxide (TMAO), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) in 161 children with ASD and 71 controls using LC-MS/MS.
• Normalized toxin concentrations to creatinine and analyzed individual levels, total burden, proportional contributions, and functional ratios (IS/PCS, PCS/TMAO, IS/ADMA).
• Conducted subgroup analyses by sex, age group, and autism severity (Childhood Autism Rating Scale - CARS).

Main Results:

• Individual toxin concentrations did not significantly differ between ASD and control groups.
• Stratified analyses showed PCS was higher in girls and severe ASD cases; IS and TMAO were reduced in younger and more severe ASD cases.
• Functional ratios shifted significantly with ASD severity: IS/PCS decreased, and PCS/TMAO increased, indicating a phenolic-dominant microbial signature and altered host-microbial balance.

Conclusions:

• Urinary uremic toxin profiles, particularly functional ratios, offer a more sensitive marker for metabolic disturbances in ASD than individual concentrations.
• These findings suggest an altered host-microbial metabolic balance in ASD, characterized by a phenolic-dominant microbial signature.
• Functional toxin profiling may enhance the characterization and understanding of metabolic alterations in autism spectrum disorder.