Dietary succinate supplementation alleviates DSS-induced colitis via the IL-4Rα/Hif-1α Axis.

Inflammatory bowel disease (IBD) remains a pressing global health challenge, necessitating novel therapeutic strategies. Succinate, a metabolite known for its role in type 2 immunity and tuft cell activation in the small intestine, presents its potential in IBD management. However, its impact on colonic inflammation has not been explored. Here, we demonstrate that succinate administration induces a type 2 immune response, significantly alleviating dextran sulfate sodium (DSS)-induced colonic inflammation. Succinate enhances antibacterial capacity, reduces intestinal permeability, and reshapes the colonic cytokine milieu. Mechanistically, succinate promotes myeloid cell expansion in peripheral blood, mesenteric lymph nodes, and the colonic lamina propria. The protective effects of succinate were abolished in Ccr2-/- mice, confirming the role of monocyte recruitment, but persisted in Rag1-/- mice, indicating independence from adaptive immunity. Adoptive transfer of monocytes from succinate-treated donors mitigated intestinal inflammation in recipient mice. Transcriptomic analysis revealed heightened expression of Il1b and Il6, and higher lactate production in monocytes upon lipopolysaccharide (LPS) stimulation, highlighting a reprogrammed pro-inflammatory trained immunity phenotype. Finally, we identify the IL-4Rα/Hif-1α axis is critical for succinate-mediated protection. These findings reveal the ability of succinate to reprogram monocytes into protective intestinal macrophages via induction of type 2 response, restoring homeostasis through enhanced barrier function and immune modulation. Our study positions thus uncover succinate as a promising therapeutic candidate for IBD.