Prospective Associations between the Sulfur Microbial Diet and Type 2 Diabetes Risk across Two Diverse Cohorts

Objective: To investigate the association between adherence to the sulfur microbial diet (SMD) and type 2 diabetes risk, and to explore dose–response relationships, effect modification, and underlying biological mechanisms.Methods: Data were obtained from two large-scale cohorts: 104,684 participants in the UK Biobank and 16,345 in the China Health and Nutrition Survey (CHNS). SMD scores were derived from dietary data based on food groups correlated with 43 sulfur-metabolizing taxa. Incident type 2 diabetes was ascertained through medical records (UK Biobank) and physician-diagnosed self-reports (CHNS). Cox models estimated hazard ratios (HRs) and 95% confidence intervals (CIs), with restricted cubic splines for dose–response relationships. Stratified and mediation analyses assessed potential modifiers and mediating biomarkers.Results: Higher SMD scores were consistently associated with a higher risk of developing type 2 diabetes (highest vs. lowest quartile: UK Biobank: HR = 1.31, 95% CI: 1.17–1.47; CHNS: HR = 3.26, 95% CI: 2.52–4.23). Spline analyses indicated a linear association in the UK Biobank and a J-shaped association in CHNS. Higher physical activity attenuated the association in CHNS (p for interaction = 0.002). Mediation analyses identified 15 circulating biomarkers spanning inflammatory, metabolic, hormonal, and hepatic pathways.Conclusion: High adherence to the SMD was associated with an increased risk of type 2 diabetes, partly mediated through diverse biological pathways. Physical activity attenuated this risk. These findings highlight the potential role of sulfur-metabolizing bacteria in glucose regulation and underscore the importance of dietary and lifestyle modification for diabetes prevention and care.