Multi-faceted characterization of the gut microbiome and metabolome in patients with primary Sjögren syndrome

The gut microbiome and its metabolomic potential in primary Sjögren syndrome (pSS) remain largely unexplored. Here, we perform whole-metagenome shotgun sequencing of fecal samples from 206 pSS patients and 355 non-pSS controls, integrating compositional and functional profiling with serum and fecal metabolomes. pSS is associated with extensive multi-kingdom alterations, including 49 bacterial (e.g., Streptococcus parasanguinis, Ligilactobacillus salivarius, and Veillonella parvula), 19 fungal (notably Candida albicans), and 1,323 viral species. These signatures form robust inter-kingdom correlations and achieve high diagnostic accuracy in an independent validation cohort. Functional and metabolomic analyses reveal enrichment of toxin-related and aromatic pathways and depletion of protective metabolites in patients. pSS-enriched bacteria harbor abundant immunogenic epitopes, virulence factors, and antimicrobial resistance genes, and induce proinflammatory responses ex vivo. Together, these findings outline a multi-faceted microbial framework for pSS and suggest mechanistic links between gut dysbiosis and immune dysregulation.