Absence of gut microbiota alleviates iron overload-induced colitis by modulating ferroptosis in mice

作者：Ke Gu, Aimin Wu, Chen Liu, Bing Yu, Jun He, Xin Lai, Junzhou Chen, Yuheng Luo, Hui Yan, Ping Zheng, Junqiu Luo, Junning Pu, Quyuan Wang, Huifen Wang, Daiwen Chen · 发表于：Journal of Advanced Research · 年份：2024 · DOI：10.1016/j.jare.2024.12.030 · 被引用次数：15 · 研究领域：Ferroptosis and cancer prognosis、Iron Metabolism and Disorders、Gut microbiota and health

INTRODUCTION: Iron overload disrupts gut microbiota and induces ferroptosis, contributing to colitis. However, whether gut microbiota directly drives iron overload-induced colitis and its underlying mechanism remain unclear. OBJECTIVES: The study aimed to explore whether gut microbiota can directly regulate iron overload-induced colitis and its underling mechanism. METHODS: Male C57BL/6N mice were fed with ferrous sulfate to establish an iron overload model. Antibiotics and dextran sulfate sodium salt (DSS) were used to create germ-free and colitis models, respectively. RESULTS: Results showed that iron overload caused disruption of systemic iron homeostasis via activating pro-inflammation response, which caused induction of ferroptosis and eventually resulted in colitis in mice. Notably, iron overload inhibited System Xc- and activated the nuclear factor E2-related factor 2/heme oxygenase-1 pathway, driving ferroptosis and colitis progression. Similar results were observed in mouse colon epithelial cells, which were treated with high doses ferric ammonium citrate. Additionally, iron overload exacerbated DSS-induced colitis by activating the ferroptosis and increasing harmful bacteria (e.g., Mucispirillum) abundance. Interestingly, eliminating gut microbiota attenuated iron overload-induced colitis, without affecting systemic inflammation through inhibiting ferroptosis of mice. Depletion of the gut microbiota partially mitigated the exacerbating effect of iron overload on DSS...