Systemic sclerosis (SSc) is a complex autoimmune disorder potentially involving gut microbial dysbiosis.This study aims to characterize the compositional and functional alterations of the gut microbiome in systemic sclerosis (SSc) patients and to explore their associations with clinical phenotypes, particularly gastrointestinal involvement.

Fecal samples were collected from 30 SSc patients and 12 healthy controls (HC) and subjected to shotgun metagenomic sequencing. Based on UCLA SCTC GIT 2.0 scores, SSc patients were further divided into two subgroups: those with gastrointestinal involvement (SSc-G+, n=17) and those without (SSc-G-, n=13). We systematically analyzed microbial diversity, taxonomic composition, functional metabolic pathways, and correlations with clinical variables including disease duration, modified Rodnan skin score (mRSS), Raynaud's phenomenon, and autoantibody profiles.

Although alpha diversity did not differ significantly among groups, beta diversity analysis revealed distinct clustering of microbial communities between HC and both SSc subgroups. At the species level, SSc patients exhibited a higher abundance of oral-origin bacteria, including Streptococcus salivarius and Streptococcus parasanguinis, indicating potential oral-gut translocation. In contrast, butyrate-producing commensals such as Roseburia inulinivorans and Faecalibacterium prausnitzii were more abundant in HC. Functional profiling identified 90 differentially enriched MetaCyc pathways in SSc, primarily involved in amino acid, vitamin, and sugar metabolism. Gut Metabolic Modules (GMMs) further revealed enhanced ethanol production and amino acid degradation capacity in SSc patients. Clinical association analysis identified 23 microbial features significantly correlated with clinical variables. Notably, Ligilactobacillus salivarius showed a positive association with Raynaud's phenomenon, suggesting a potential link between specific microbes and vascular manifestations in SSc.

Our findings demonstrate that SSc is associated with distinct gut microbial dysbiosis characterized by oral-to-gut translocation and significant metabolic alterations. These microbial signatures correlate with specific clinical features, suggesting they may contribute to disease pathogenesis and clinical heterogeneity. The depletion of butyrate-producers and enrichment of opportunistic oral species may represent potential therapeutic targets. Further studies with larger, longitudinal cohorts are warranted to validate these observations, establish causal relationships, and explore the translational potential of microbiome-based biomarkers or interventions in SSc management.