Dihydroartemisinin alleviates ulcerative colitis by modulating gut microbiota and butyrate to restore Treg/Th17 balance and intestinal barrier function.

Accumulating evidence suggests that dihydroartemisinin (DHA), a natural compound known for its anti-inflammatory and immunomodulatory properties, holds therapeutic potential for ulcerative colitis (UC). However, its mechanism of action, particularly concerning the gut microbiota and its metabolites, remains incompletely understood. In this study, we evaluated the therapeutic effects of dihydroartemisinin in a dextran sulfate sodium (DSS)-induced murine model of UC. Dihydroartemisinin was administered at doses of 10, 20, and 50 mg/kg, with 5-aminosalicylic acid (5-ASA, 50 mg/kg) serving as a positive control. The 50 mg/kg dose demonstrated the most pronounced efficacy and was thus selected for subsequent mechanistic investigation. Results demonstrated that dihydroartemisinin treatment significantly ameliorated colitis in a dose-dependent manner, as indicated by improved body weight, reduced disease activity index, increased colon length, and attenuated histopathological damage. 16S rRNA sequencing revealed that dihydroartemisinin restored gut microbial diversity and promoted the enrichment of butyrate-producing bacteria, including Eubacterium siraeum. GC-MS analysis confirmed a specific increase in fecal butyrate levels. Transcriptomic analysis showed that dihydroartemisinin reversed DSS-induced dysregulation of colonic gene expression, upregulating pathways related to tight junction assembly, mucin biosynthesis, and anti-inflammatory responses, while suppressing pro-inflammatory signaling. Furthermore, dihydroartemisinin administration rebalanced the Treg/Th17 cell ratio, reduced levels of pro-inflammatory cytokines (IL-6, IL-17 A, IL-1β, MCP-1), and enhanced anti-inflammatory mediators (IL-10, FOXP3). Additionally, dihydroartemisinin enhanced goblet cell function, upregulated mucin secretion (MUC2, TFF3), and increased the expression of tight junction proteins (ZO-1, Occludin). These results indicate that dihydroartemisinin alleviates experimental colitis primarily by modulating the gut microbiota-butyrate-Treg/Th17 axis and reinforcing intestinal barrier function. Our findings support the potential of dihydroartemisinin as a therapeutic agent for UC and provide novel insights into its mechanism of action.