Genetically predicted artificial sweeteners and stroke susceptibility: a multivariable Mendelian randomization study

The present study investigated the causal associations of artificial sweetener consumption on the risk of stroke. We applied a two-sample Mendelian randomization (MR) design using genome-wide association study (GWAS) summary data for artificial sweetener intake (added to coffee, tea, and cereal) and stroke. The primary inverse variance weighted (IVW) analysis was complemented by sensitivity tests (Cochran’s Q-test, MR-Egger, MR-PRESSO, and leave-one-out analysis) and multivariate MR (MVMR) to address heterogeneity, pleiotropy, and potential confounding. Artificial sweeteners added to tea nominally increased small vessel stroke risk (OR = 3.01, 95%CI: 1.28–7.07, p = 0.0115, P-FDR = 0.20). Low-calorie drink intake (OR = 1.71, 95%CI: 1.12–2.63, p = 0.014, P-FDR = 0.20) and sucralose metabolite levels (OR = 1.14, 95%CI: 1.02–1.27, p = 0.029, P-FDR = 0.20) were nominally associated with cardioembolic stroke. MVMR analysis revealed that after adjusting for coffee intake, the association between intake of artificial sweeteners added to tea and small vessel stroke (OR = 2.90, p = 0.024) remained statistically significant. And after adjusting for blood glucose levels, the association between sucralose metabolite levels and cardioembolic stroke reversed direction and remained statistically significant (OR = 0.73, p = 0.024). This MR study indicated that artificial sweeteners, particularly those added to tea and sucralose metabolites, were associated with small vessel and cardioembolic stroke, respectively. However, these associations were attenuated after adjusting for BMI or tea consumption, indicating potential confounding by adiposity or beverage habits. Findings should be interpreted cautiously and warrant further investigation.