Sodium cyclamate aggravates DSS-induced colitis in mice with associated microbial, metabolic, and epithelial alterations.

Abstract

Sodium cyclamate is widely used as a non-nutritive sweetener, but its effects during intestinal inflammation remain poorly defined. We investigated whether chronic cyclamate exposure aggravated dextran sulfate sodium (DSS)-induced colitis in mice using disease phenotyping, 16S rRNA gene sequencing, targeted short-chain fatty acid and bile acid measurements, metabolomics, lipidomics, discovery proteomics, and independent western blot validation. Relative to DSS alone, DSS + Cyclamate mice exhibited greater disease severity and higher abundances of Bacteroides and Klebsiella; Lactobacillus and Muribaculaceae showed only nonsignificant downward trends in the direct comparison. Short-chain fatty acids and colonic bile acids did not differ significantly between DSS and DSS + Cyclamate, indicating that these changes provided contextual information rather than evidence for a primary cyclamate-specific pathway. The direct multi-omics comparison identified candidate alterations in central carbon and mitochondrial metabolism, purine metabolism, lipid remodeling, epithelial homeostasis, and redox defense. Western blotting confirmed lower Mucin-2, Occludin, glutathione peroxidase 2 (GPX2), and thioredoxin 2 (TXN2) abundance and higher total protein kinase C-β (PKC-β) abundance in DSS + Cyclamate mice. Changes in hypoxanthine, diacylglycerols (DAG), and cyclohexylamine supported testable hypotheses. These findings indicate that cyclamate exposure can aggravate DSS-induced colitis and identify microbial, epithelial, redox, and lipid-associated processes for causal validation.