BackgroundThe link between the gut microbiota (GM) and Sjögren’s Syndrome (SS) is well-established and apparent. Whether GM is causally associated with SS is uncertain.MethodsThe MiBioGen consortium’s biggest available genome-wide association study (GWAS) meta-analysis (n=13,266) was used as the basis for a two-sample Mendelian randomization study (TSMR). The causal relationship between GM and SS was investigated using the inverse variance weighted, MR-Egger, weighted median, weighted model, MR-PRESSO, and simple model methods. In order to measure the heterogeneity of instrumental variables (IVs), Cochran’s Q statistics were utilized.ResultsThe results showed that genus Fusicatenibacter (odds ratio (OR) = 1.418, 95% confidence interval (CI), 1.072–1.874, P = 0.0143) and genus Ruminiclostridium9 (OR = 1.677, 95% CI, 1.050–2.678, P = 0.0306) were positively correlated with the risk of SS and family Porphyromonadaceae (OR = 0.651, 95% CI, 0.427–0.994, P = 0.0466), genus Subdoligranulum (OR = 0.685, 95% CI, 0.497–0.945, P = 0.0211), genus Butyricicoccus (OR = 0.674, 95% CI, 0.470–0.967, P = 0.0319) and genus Lachnospiraceae (OR = 0.750, 95% CI, 0.585–0.961, P = 0.0229) were negatively correlated with SS risk using the inverse variance weighted (IVW) technique. Furthermore, four GM related genes: ARAP3, NMUR1, TEC and SIRPD were significant causally with SS after FDR correction (FDR<0.05).ConclusionsThis study provides evidence for either positive or negative causal effects of GM composition and its related genes on SS risk. We want to provide novel approaches for continued GM and SS-related research and therapy by elucidating the genetic relationship between GM and SS.