Gut microbiome-metabolome dysregulation in systemic sclerosis: a multi-omics study.

Abstract

The interplay between the gut microbiome (GM), plasma metabolites and systemic sclerosis (SSc) has not been systematically studied. We hypothesized that disruption at the GM-metabolome interface contributes to the pathogenesis of SSc. This study aims to investigate the faecal microbiome composition and plasma metabolite profiles in SSc patients. To evaluate the interactions, deep shotgun metagenomic sequencing was conducted on faecal samples from 15 SSc patients and 33 healthy controls. Simultaneously, untargeted liquid chromatography-tandem mass spectrometry metabolomic profiling was performed on plasma samples from 14 SSc patients and 30 controls. The analysis revealed significant alterations in 11 microbial species and 266 MS2-identified metabolites in SSc patients vs controls. In SSc, elevated levels of Escherichia coli, Lactobacillus mucosae and Parabacteroides distasonis were noticed. Conversely, Phocaeicola plebeius, Blautia hansenii and Agathobaculum butyriciproducens were enriched in the control group. Functional predictions indicated a depletion of amino acid biosynthesis pathways, including L-isoleucine and L-methionine, in SSc patients. The metabolomic analysis demonstrated a significant reduction in lipid-like molecules and amino acid levels in SSc patients. Dysregulated pathways, such as alanine, aspartate and glutamate metabolism, arginine and proline metabolism, and glycine, serine and threonine metabolism, were associated with the development of SSc. Striking microbiota-metabolite correlations (168 significant associations) were identified, with disease-enriched species showing specific metabolic linkages. This study offers a comprehensive characterization of the disrupted GM-metabolite interface in SSc patients, providing new perspectives on SSc pathogenesis and potential therapeutic targets.