Artificial Sweeteners and Autoimmune Diseases: Insights From Integrative Bioinformatics and Mendelian Randomization

Artificial sweeteners (AS) are widely used food additives, yet their potential role in autoimmune diseases (ADs) remains poorly understood. In this study, we integrated toxicological prediction, Mendelian randomization (MR), bioinformatics analyses, molecular docking, and gut microbiota assessment to investigate the association between AS exposure and ADs and to identify potential underlying mechanisms. Toxicity prediction using the ProTox-II server indicated a high immunotoxic potential for AS (> 0.9). MR analysis revealed a positive association between artificially sweetened cereal consumption and ADs risk (OR = 1.223, 95% CI: 1.005-1.488, p = 0.04). A total of 209 AS-related genes (ARGs) were identified through target prediction databases. Functional enrichment analyses demonstrated that these genes were primarily involved in apoptosis, TNF signaling, and IL-17 signaling pathways, suggesting their contribution to immune dysregulation. By integrating maximal clique centrality (MCC) algorithms with MR evidence, six core targets, including EPHX2, ESR1, ITGB3, MMP9, IL2RA, and PIM1, were identified as potential mediators of AS-associated ADs. Molecular docking further supported the binding affinity between AS compounds and these target proteins. In addition, gut microbiota analysis suggested that AS may suppress beneficial bacteria such as Akkermansia muciniphila, thereby disrupting arachidonic acid metabolism and chemokine signaling pathways involved in autoimmune pathogenesis. Collectively, these findings establish a multi-omics framework linking AS exposure to autoimmune dysregulation and provide novel insights into the immunotoxicological effects of AS and their potential role in the development of ADs.