Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; Animal Disease Prevention and Control and Healthy Breeding Engineering Technology Research Centre, Mianyang Normal University, Mianyang 621000, China.
Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China.
Ecotoxicol Environ Saf. 2024 Apr 15;275:116241. doi: 10.1016/j.ecoenv.2024.116241. Epub 2024 Mar 23.
Iron overload occurs due to excessive iron intake compared to the body's demand, leading to iron deposition and impairment of multiple organ functions. Our previous study demonstrated that chronic oral administration of ferric citrate (FC) caused colonic inflammatory injury. However, the precise mechanism underlying this inflammatory response remains unclear. The current study aims to investigate the mechanism by which iron overload induced by FC exposure leads to colonic inflammation. To accomplish this, mice were orally exposed to three different concentrations of FC (71 mg/kg/bw (L), 143 mg/kg/bw (M) and 286 mg/kg/bw (H)) for continuous 16 weeks, with the control group receiving ultrapure water (C). Exposure to FC caused disturbances in the excretory system, altered colonic flora alpha diversity, and enriched pathogenic bacteria, such as Mucispirillum, Helicobacter, Desulfovibrio, and Shigella. These changes led to structural disorders of the colonic flora and an inflammatory response phenotype characterized by inflammatory cells infiltration, atrophy of intestinal glands, and irregular thickening of the intestinal wall. Mechanistic studies revealed that FC-exposure activated the NF-κB signaling pathway by up-regulating TLR4, MyD88, and NF-κB mRNA levels and protein expression. This activation resulted in increased production of pro-inflammatory cytokines, further contributing to the colonic inflammation. Additionally, in vitro experiments in SW480 cells confirmed the activation of NF-κB signaling pathway by FC exposure, consistent with the in vivo findings. The significance of this study lies in its elucidation of the mechanism by which iron overload caused by FC exposure leads to colonic inflammation. By identifying the role of pathogenic bacteria and the NF-κB signaling pathway, this study could potentially offer a crucial theoretical foundation for the research on iron overload, as well as provide valuable insights for clinical iron supplementation.
铁过载是由于机体摄入的铁超过了其需求，导致铁沉积和多个器官功能受损。我们之前的研究表明，柠檬酸铁（FC）的慢性口服给药会导致结肠炎症损伤。然而，这种炎症反应的确切机制仍不清楚。本研究旨在探讨 FC 暴露引起的铁过载导致结肠炎症的机制。为此，我们用三种不同浓度的 FC（71mg/kg/bw（低）、143mg/kg/bw（中）和 286mg/kg/bw（高））连续口服暴露小鼠 16 周，对照组给予超纯水（C）。FC 暴露导致排泄系统紊乱，改变了结肠菌群的α多样性，并富集了致病性细菌，如 Mucispirillum、Helicobacter、Desulfovibrio 和 Shigella。这些变化导致结肠菌群结构紊乱，并表现出以炎症细胞浸润、肠腺萎缩和肠壁不规则增厚为特征的炎症反应表型。机制研究表明，FC 暴露通过上调 TLR4、MyD88 和 NF-κB mRNA 水平和蛋白表达，激活 NF-κB 信号通路。这种激活导致促炎细胞因子的产生增加，进一步导致结肠炎症。此外，SW480 细胞的体外实验证实了 FC 暴露激活 NF-κB 信号通路，与体内研究结果一致。本研究的意义在于阐明 FC 暴露导致铁过载引起结肠炎症的机制。通过确定致病性细菌和 NF-κB 信号通路的作用，本研究可能为铁过载的研究提供重要的理论基础，并为临床铁补充提供有价值的见解。
