To investigate the bidirectional causal relationships between SS and seven common GI diseases—gastric ulcer (GU), duodenal ulcer (DU), irritable bowel syndrome (IBS), Crohn's disease (CD), ulcerative colitis (UC), non-infectious gastroenteritis (NGE), and constipation (CP)—using a two-sample Mendelian randomization (MR) approach.

Genetic instruments for SS and GI diseases were selected from large-scale genome-wide association study (GWAS) summary statistics, including data from FinnGen (3,309 SS cases; 484,260 controls) and publicly available consortia. Single nucleotide polymorphisms (SNPs) associated with exposures at a suggestive significance threshold (P < 5×10⁻⁶) were used as instrumental variables after rigorous quality control, including linkage disequilibrium clumping, F-statistic calculation (all F > 10), and pleiotropy screening. Inverse variance weighted (IVW) regression served as the primary analytical method, complemented by MR-Egger, weighted median, and weighted mode approaches. Sensitivity analyses, including Cochran's Q test, MR-Egger intercept test, MR-PRESSO, and leave-one-out analysis, were performed to assess heterogeneity and horizontal pleiotropy.

Genetically predicted SS was associated with a significantly increased risk of GU (IVW OR = 1.055, 95% CI: 1.013–1.100, P = 0.011), an effect consistently supported by all sensitivity analyses. Conversely, SS demonstrated a protective effect against IBS (IVW OR = 0.970, 95% CI: 0.948–0.993, P = 0.012). No causal effects of SS were observed for DU, CD, UC, NGE, or CP. In reverse MR analysis, genetic predisposition to NGE significantly increased the risk of developing SS (IVW OR = 1.347, 95% CI: 1.118–1.622, P = 0.0017), with directional consistency across complementary methods and no evidence of pleiotropy. No significant causal effects were identified for other GI diseases on SS risk.

This study provides novel evidence for bidirectional causal relationships between SS and specific GI disorders: SS increases GU risk while reducing IBS susceptibility, and NGE contributes to SS development. These findings highlight the importance of GI surveillance in SS management and suggest that gut-immune interactions may play a role in SS pathogenesis. Further research is warranted to elucidate the underlying mechanisms, including the potential role of gut microbiota and mucosal immunity.