Multi-omics characterization of gut microbiota and fecal and plasma metabolites in patients with primary Sjögren's syndrome.

Introduction: Accumulating evidence has implicated gut microbiota and their metabolites in primary Sjögren's syndrome (pSS) pathogenesis. However, no study simultaneously explores the gut microbiome, microbial, and plasma metabolome in pSS patients.

Method: Thirty pSS patients and 60 healthy controls (HCs) were recruited. Shotgun metagenomic sequencing and untargeted metabolomics were performed on stool and plasma samples.

Results: pSS patients exhibited significant reduction in microbial richness and diversity. Bacteroidetes and Firmicutes accounted for over 80% of all phyla. Four phyla, 48 genera, and 106 species with significant differences were identified (P < 0.05). Proteobacteria, Ascomycota, Fusobacteria, and 31 genera (e.g., Escherichia, Veillonella, Prevotella, Klebsiella) were enriched in pSS, while Actinobacteria, Bifidobacterium, Dorea, and Blautia were depleted. Opportunistic pathogens (e.g., Escherichia coli, Prevotella copri, Streptococcus oralis, Klebsiella pneumoniae, Enterococcus faecalis) and pathogenic Clostridium bolteae and Fusobacterium nucleatum were more abundant in pSS, whereas beneficial Bifidobacterium longum and butyrate-producing Eubacterium hallii and Anaerostipes hadrus were in HCs. Notably, Lactobacillus spp. were enriched in pSS. Of 298 differential functional pathways, 239 pSS-enriched pathways were focused on nutrient and energy metabolism, while amino acid biosynthesis in HCs. During 881 differential fecal metabolites (pSS: HCs = 631:250), fatty acyls were enriched in pSS, and glycerophospholipids in HCs. Among the 712 differential plasma metabolites (pSS: HCs = 438:274), heterocyclic compounds and benzene derivatives were more abundant in pSS, while fatty acyls and glycerophospholipids prevailed in HCs. Amino acids and organic acids were predominant in both samples.

Conclusions: This study characterized gut microbiome and fecal/plasma metabolome in pSS patients, providing theoretical support for regional pSS prevention and treatment. Key Points • This is the first study to systematically characterize the gut microbiome and fecal and plasma metabolomes of primary Sjögren's syndrome (pSS) patients in Northwest China via multi-omics integration analysis. • Significant reduction in gut microbial diversity and probiotic bacteria, enrichment of opportunistic and infectious pathogens, and microbial dysfunction were observed in pSS patients. • Much more differential fecal and plasma metabolites were observed in pSS patients, with amino acids, organic acids and derivatives, nucleotides, and metabolites being the main altered metabolites in both samples.