Community Modeling Reveals Disrupted Gut Microbial Secretion in Autism Associated With Redox and Neurometabolic...

Area of Science:

• Microbiome research
• Neuroscience
• Metabolomics

Background:

• Disruptions in the gut microbiome are increasingly linked to autism spectrum disorder (ASD) via altered microbial metabolism and gut-brain communication.
• The precise metabolic consequences of these microbial shifts in ASD remain largely undefined.

Purpose of the Study:

• To investigate the specific metabolic impacts of gut microbiome alterations in children with ASD.
• To predict host-impacting metabolite secretion using community-scale metabolic modeling.
• To evaluate the effects of microbiota transfer therapy (MTT) on microbial metabolism and ASD severity.

Main Methods:

• Shotgun metagenomics data from children with ASD and neurotypical controls were analyzed using community-scale metabolic modeling.
• Predicted metabolite secretion profiles were compared between ASD and control groups.
• Fecal metabolomics data were used for empirical validation.
• Changes in metabolite profiles following MTT were assessed in relation to autism severity scores.

Main Results:

• Modeled ASD-associated microbial communities showed altered predicted secretion of metabolites involved in redox balance and neurotransmission, including increased 2-ketobutyrate and GABA, and decreased riboflavin and inositol.
• Microbiota transfer therapy (MTT) shifted these predicted metabolic profiles towards those of neurotypical individuals.
• Empirical fecal metabolomics generally supported the model's predictions.
• Reduced autism severity after MTT correlated with increased predicted secretion of inositol and arginine.
• ASD microbiomes exhibited a depletion of beneficial taxa and an enrichment of pro-inflammatory species like Escherichia.

Conclusions:

• Microbial metabolism is a significant contributor to autism spectrum disorder traits.
• Targeting microbial metabolism through interventions like MTT represents a promising therapeutic strategy for ASD.
• Specific microbial taxa and their associated neuroactive metabolites offer potential targets for modulating ASD symptoms.