Family-based multi-omics reveal gut dysbiosis and circulatory metabolic disruption in amyotrophic lateral sclerosis

ABSTRACT:

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with unclear etiology and no effective cure. Accumulating evidence implicates gut microbiota dysbiosis and circulatory metabolic al-terations in ALS pathogenesis, potentially driving disease progression and severity.

Methods: We enrolled 36 ALS patients and 32 healthy household relatives of these ALS patients as controls to minimize environmental confounders. Fecal (n=61) and serum (n=68) samples were analyzed using metagenomic sequencing for gut microbiota composition and untargeted metabolomics for fecal and serum metabolic profiles. Statistical and machine learning approaches, including principal coordinate analysis (PCoA), linear discriminant analysis effect size (LEfSe), and random forest modeling, identified differentially abundant taxa, metabolites, and biomarkers.

Results: ALS gut microbiota showed distinct beta diversity but unchanged alpha diversity. Pathogenic Proteobacteria (Enterobacteriaceae, Desulfovibrioaceae) increased, while beneficial Faecalibacterium and Clostridium decreased. A random forest model identified 20 microbial genera (AUC=0.89) and species (AUC=0.92) as ALS biomarkers. Microbial functions indicated hyperactive carbohydrate and amino acid metabolism and suppressed fatty acid metabolism. Fecal metabolomics revealed 722 altered metabolites (670 downregulated, e.g., lipids; 52 upregulated), disrupting phenylpropanoid biosynthesis and linoleic acid metabolism. Serum metabolomics showed lipid and choline metabolism perturbations. Reduced creatine and 2-hydroxybutyrate correlated with lower ALS Functional Rating Scale-Revised scores, while elevated diacylglycerols tracked disease severity. Symbiotic network analysis linked pathogenic Erysipelatoclostridium to reduced beneficial metabolites. Eubacterium was a central node, influencing metabolomes and BMI, with higher BMI correlating with Firmicutes enrichment (e.g., Ruminococcus).

Conclusion: ALS patients exhibit gut microbiota dysbiosis and circulatory metabolic disruptions, shaped by host factors like BMI and disease severity, correlating with disease progression. The microbiota-metabolite axis, elucidated through multi-omics and network analyses, offers targets for non-invasive biomarkers and therapies like microbiota modulation.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS13295 | MetaboLights | 2026-04-07

REPOSITORIES: MetaboLights