Abstract
BACKGROUND: This study investigates the potential interplay between gut microbiota and circulating cytokines in Sjögren's syndrome (SS) through a bidirectional and mediation Mendelian randomization (MR) approach. METHODS: Summary-level statistics of 473 gut microbiota (n = 5959), 41 circulating cytokines (n = 8293), and SS (ncase = 2735, ncontrol = 399,355) were obtained from genome-wide association studies (GWAS) in European populations. A two-sample MR analysis was employed to investigate the bidirectional causal effects of gut microbiota and circulating cytokines on SS, and mediation analyses were applied to discover potential mediating gut microbiota and circulating cytokines. A series of sensitivity analyses were conducted to address heterogeneity and pleiotropy concerns. RESULTS: Fifteen taxa were found to be causally associated with SS, and SS had a causal effect on 26 taxa. A bidirectional causal relationship was identified between CAG-269 sp001916065 and SS, and between UBA7703 and SS. Genetically predicted levels of five circulating cytokines-MIG, IL-5, IL-1RA, IL-2RA, and SCGF-β-were found to potentially affect SS, and genetically predicted SS was associated with increased levels of two circulating cytokines, IL-1β and IL-5. A bidirectional causal relationship was identified between circulating IL-5 and SS. Mediation analyses further revealed that circulating cytokines do not mediate the gut microbiome's influence on SS, and conversely, the gut microbiome does not influence circulating cytokines to affect SS. CONCLUSION: This study provides compelling evidence for causal effects of gut microbiome composition and circulating cytokines on SS risk. Further mediation analysis suggests that these biological factors may operate independently to influence SS development.