Dietary Succinate Supplementation Alleviates DSS-Induced Colitis via the IL-4Ra/Hif-1a Axis

Succinate administration induced characteristic type 2 immunity via the tuft cell-ILC2 immune circuit, significantly ameliorating DSS-induced colonic inflammation by enhancing bactericidal capacity, reducing intestinal permeability, and modulating cytokine profiles in the colon. Succinate promoted expansion of myeloid cells in peripheral blood, mesenteric lymph nodes (MLN), and colonic lamina propria. The protective effect of succinate was abolished in Ccr2-/- mice but maintained in Rag1-/- mice. Adoptive transfer of monocytes from succinate-treated donors to naïve recipient mice mitigated intestinal inflammation. RNA-seq revealed increased expression of proinflammatory cytokines IL-1ß, IL-6, and lactate upon lipopolysaccharide (LPS) stimulation in monocytes from succinate-treated mice. Moreover, the critical role of the IL-4Ra/Hif-1a axis in succinate-mediated protection was delineated. Overall design: Mice were treated with or without 300 mM succinate for 7 days, and CD11b+Ly6Chi monocytes from bone marrow were sorted, then stimulated in presence or absence of LPS in vitro.And monocyte total RNA was extracted for RNA-seq