The Role of Inflammatory Cytokines in the Causal Pathway From Gut Microbiota to Sjögren’s Syndrome: Evidence From Mendelian Randomization
Mediators of Inflammation, 2025
Zhao J., Han J., Fan X., Kang J., Wu R., Zhao Y., Bai L., Gao X., Ma D., Zhang L.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Immunological & Inflammatory Diseases | Pathophysiology | Plasma |  Olink Target 96 |
Abstract
Purpose
Evidence is accumulating that links gut microbiota, a crucial component of the immune environment, to Sjogren’s syndrome (SS). The mechanisms underlying the influence of gut microbiota on the onset and development of SS are still not completely understood. To this end, we applied a Mendelian randomization (MR) framework to investigate whether inflammatory cytokines mediate the association of gut microbiota with SS.
Methods
Our MR analysis leveraged publicly available GWAS data, including information on 211 gut microbiota taxa sourced from the MiBioGen consortium (18,340 participants), summary statistics for 91 inflammatory cytokines obtained from a study of 14,824 individuals, and genetic data for SS derived from the UK Biobank (407,746 participants). To investigate causal associations between gut microbiota and SS, we primarily employed the inverse variance weighted method, supported by additional techniques such as MR‐Egger, simple mode, weighted median, and weighted mode for validation. The potential mediating effect of inflammatory cytokines in the gut microbiota–SS relationship was investigated using both mediation MR and multivariable MR (MVMR) analyses.
Results
MR analysis identified five microbiota taxa causally associated with SS. Particularly, class Gammaproteobacteria (OR = 3.468, 95% CI = 1.139–10.557, p = 0.029) and genus Peptococcus (OR = 1.722, 95% CI = 1.082–2.471, p = 0.022) were significantly associated with an increased risk of developing SS. Six inflammatory cytokines were identified as potentially causal, with Axin‐1 (OR = 2.556, 95% CI = 1.072–6.096, p = 0.034) and C‐X‐C motif chemokine 10 levels (CXCL10) (OR = 3.049, 95% CI = 1.428–6.513, p = 0.004) being the most critical contributors. Mediation MR analysis showed that Axin‐1 levels mediated 16.96% of the causal effect of class Gammaproteobacteria on SS, CXCL10 levels mediated 36.78% of the causal effect of genus Coprococcus3 on SS.
Conclusion
The findings suggest that certain gut microbiota is sociated with an increased risk of SS, mediated by specific inflammatory cytokines.