pSS is associated with extensive multi-kingdom gut microbiome alterations including 49 bacterial, 19 fungal, and 1,323 viral species, which form robust inter-kingdom correlations, achieve high diagnostic accuracy, and suggest mechanistic links between gut dysbiosis and immune dysregulation.
Key Findings
Results
Primary Sjögren syndrome is associated with significant alterations in gut bacterial composition, with 49 differentially abundant bacterial species identified.
Whole-metagenome shotgun sequencing was performed on fecal samples from 206 pSS patients and 355 non-pSS controls.
Notable pSS-enriched bacteria included Streptococcus parasanguinis, Ligilactobacillus salivarius, and Veillonella parvula.
Both compositional and functional profiling were integrated in the analysis.
Findings were validated in an independent validation cohort.
Results
pSS is associated with significant alterations in gut fungal and viral communities, including 19 differentially abundant fungal species and 1,323 viral species.
Candida albicans was notably enriched among the 19 fungal species altered in pSS.
1,323 viral species were identified as differentially represented in pSS patients versus controls.
This represents a multi-kingdom characterization encompassing bacteria, fungi, and viruses.
The study used whole-metagenome shotgun sequencing enabling simultaneous detection across kingdoms.
Results
The multi-kingdom microbial signatures in pSS form robust inter-kingdom correlations and achieve high diagnostic accuracy in an independent validation cohort.
Bacterial, fungal, and viral signatures were shown to be correlated with each other across kingdoms.
The microbial signatures demonstrated high diagnostic accuracy when tested in an independent validation cohort.
Both compositional profiles and functional profiles contributed to the diagnostic framework.
The study integrated serum and fecal metabolomes alongside microbiome data.
Results
Functional and metabolomic analyses revealed enrichment of toxin-related and aromatic pathways and depletion of protective metabolites in pSS patients.
Both serum and fecal metabolomes were analyzed and integrated with metagenomic data.
Toxin-related pathways were enriched in the gut microbiome of pSS patients.
Aromatic compound metabolic pathways were also enriched in pSS patients.
Protective metabolites were depleted in pSS patients compared to controls.
Results
pSS-enriched bacteria harbor abundant immunogenic epitopes, virulence factors, and antimicrobial resistance genes, and induce proinflammatory responses ex vivo.
Immunogenic epitopes were identified in pSS-enriched bacterial species, suggesting potential for immune activation.
Virulence factors and antimicrobial resistance genes were also identified in pSS-enriched bacteria.
Ex vivo experiments demonstrated that pSS-enriched bacteria induced proinflammatory responses.
These findings suggest mechanistic links between gut dysbiosis and the immune dysregulation characteristic of pSS.
Methods
The study employed a large-scale multi-omics design integrating whole-metagenome shotgun sequencing with serum and fecal metabolomics across a substantial patient cohort.
206 pSS patients and 355 non-pSS controls were included in the discovery cohort.
Whole-metagenome shotgun sequencing (WMGS) of fecal samples was performed.
Both serum and fecal metabolomes were profiled and integrated with microbiome data.
An independent validation cohort was used to confirm diagnostic accuracy of identified signatures.
What This Means
This research suggests that patients with primary Sjögren syndrome (pSS), an autoimmune disease that causes dry eyes and dry mouth among other symptoms, have widespread and distinctive differences in their gut microbiome compared to healthy individuals. By analyzing stool samples from 206 pSS patients and 355 controls using advanced DNA sequencing, researchers identified 49 altered bacterial species, 19 altered fungal species, and over 1,300 altered viral species in the guts of pSS patients. These changes were not limited to one type of microorganism but spanned bacteria, fungi, and viruses simultaneously, and the different microbial communities appeared to influence each other in a coordinated way.
The study also found that the altered gut microbiome in pSS patients is functionally distinct — it produces more toxin-related compounds and fewer protective molecules compared to healthy individuals. The bacteria that are more abundant in pSS patients carry features that could trigger immune responses, including structures that the immune system recognizes as foreign, as well as genes that help bacteria resist antibiotics and cause disease. When these bacteria were tested in laboratory experiments, they provoked inflammatory immune responses, providing a plausible biological mechanism connecting gut microbiome changes to the immune system problems seen in pSS.
This research suggests that gut microbiome dysbiosis — an imbalance in the microbial communities living in the gut — may play an important role in pSS, potentially contributing to or worsening the immune dysfunction that underlies the disease. The multi-kingdom microbial signatures were also shown to accurately identify pSS patients in an independent group of participants, suggesting these microbiome patterns could potentially serve as diagnostic biomarkers. These findings open new avenues for understanding pSS and may eventually inform new therapeutic strategies targeting the gut microbiome.
Chen C, Xing Y, Xing G, Zeng F, Zheng N, Sha S, et al.. (2026). Multi-faceted characterization of the gut microbiome and metabolome in patients with primary Sjögren syndrome.. Cell reports. Medicine. https://doi.org/10.1016/j.xcrm.2026.102777