Dietary Succinate Supplementation Alleviates DSS-Induced Colitis via the IL-4Rα/Hif-1α 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-1β, IL-6, and lactate upon lipopolysaccharide (LPS) stimulation in monocytes from succinate-treated mice. Moreover, the critical role of the IL-4Rα/Hif-1α axis in succinate-mediated protection was delineated. 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

琥珀酸给药可通过簇细胞-固有淋巴细胞2型（ILC2）免疫环路诱导特征性2型免疫应答，通过增强杀菌能力、降低肠道通透性以及调控结肠内细胞因子谱，显著改善葡聚糖硫酸钠（DSS）诱导的结肠炎症。琥珀酸可促进外周血、肠系膜淋巴结（MLN）以及结肠固有层中髓系细胞的增殖扩增。琥珀酸的保护作用在Ccr2基因敲除（Ccr2-/-）小鼠中被完全消除，但在Rag1基因敲除（Rag1-/-）小鼠中得以保留。将经琥珀酸处理的供体小鼠单核细胞过继转移至未致敏受体小鼠体内，可缓解肠道炎症。转录组测序（RNA-seq）结果显示，经琥珀酸处理的小鼠的单核细胞在脂多糖（LPS）刺激下，促炎细胞因子IL-1β、IL-6以及乳酸的表达水平均显著升高。此外，本研究还阐明了IL-4Rα/Hif-1α信号轴在琥珀酸介导的保护作用中的关键功能。实验中，小鼠被分为两组，分别连续7天给予300 mM琥珀酸处理或不作处理；随后从骨髓中分选得到CD11b+Ly6Chi单核细胞，在体外分别予以脂多糖（LPS）刺激或不进行刺激，最后提取单核细胞总RNA用于转录组测序（RNA-seq）。