Mechanistic insights into sucralose immunotoxicology: Dose-related modulation of the gut-immune axis in food allergy.

Sucralose is a widely consumed non-caloric sweetener, but its immunotoxicological effects remain poorly defined. Integrated in vitro and in vivo methods were utilized to investigate its immunotoxicological profile. In vitro, sucralose suppressed dendritic cell maturation and IL-6 secretion, promoted the differentiation of naïve CD4+ T cells into Th1 cells, and reshaped cytokine profiles in DC-T cell co-cultures. In the food allergy model of ovalbumin (OVA)-induced BALB/c mice, the treated dose chronic dietary intake of sucralose at 10× the acceptable daily intake (ADI) exerted a surprising immunomodulatory effect, but did not at the dose of ADI. Compared to the OVA allergy group, treatment with the 10×ADI dose of sucralose alleviated allergic symptoms, suppressed serum levels of IgE/IgG1/mMCP-1, restored intestinal barrier function, shifted the Th1/Th2 balance toward Th1 dominance, and inhibited mast cell activation. Multi-omics integration revealed that the 10×ADI dose concurrently modulated immune and microbial axes, with downregulation of pro-allergic mediators (Edn1, Chrm2) within the cAMP signaling pathway and enrichment of beneficial gut microbiota (Lactobacillus), providing mechanistic evidence for a dose threshold at which sucralose engages the gut-immune axis. These findings demonstrated that sucralose exhibited dose-related immunomodulatory activity, providing a more nuanced basis for some food additives safety assessment.