Oral administration of liquid iron preparation containing excess iron induces intestine and liver injury, impairs intestinal barrier function and alters the gut microbiota in rats
Oral administration of liquid iron preparation containing excess iron induces intestine and liver injury, impairs intestinal barrier function and alters the gut microbiota in rats
复制标题
口服含过量铁的液态铁制剂会引起大鼠肠道和肝脏损伤，损害肠道屏障功能并改变肠道微生物群
DOI：
10.1016/j.jtemb.2018.01.002
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发表时间：
2018-01-01
影响因子：
3.5
通讯作者：
Feng, Jie
中科院分区：
文献类型：
--
作者：
Fang, Shenglin;Zhuo, Zhao;Feng, Jie
本研究的目的是确定液体铁制剂中过量铁的毒理学效应（特别是对肠屏障功能）以及过量铁引起的副作用或疾病的可能病因。实验一：40只4-5周龄雄性SD大鼠，分别灌胃给予1 ml溶媒（0.01 mol/L盐酸）或1 ml含8 mg、16 mg和24 mg铁的液体铁制剂30 d。铁状态，氧化应激，组织学（H&E染色），超微结构（电子显微镜）和细胞凋亡（TUNEL法）在肠道和肝脏进行了评估。通过16 S rRNA测序评价盲肠微生物群。在研究2中，20只具有上述特征的大鼠经口灌胃1 ml溶剂或24 mg Fe，持续30 d。通过体内研究和Ussing室试验测定肠屏障功能;通过酶联免疫吸附试验观察紧密连接蛋白和血清促炎细胞因子。在研究1中，肠粘膜和肝脏表现出明显的氧化应激。此外，铁浓度依赖性的超微结构的改变，十二指肠肠上皮细胞和肝细胞和结肠粘膜的组织学损伤进行了检测。值得注意的是，十二指肠上皮细胞和肝细胞凋亡增加。观察到肠屏障功能受损和肠紧密连接蛋白表达降低，并且结肠中的表型比十二指肠中的表型更严重。血清促炎细胞因子表达增高的趋势可能提示全身性炎症。此外，盲肠微生物群显示出显著变化，其中Defluviitaleaceae，Ruminococcaceae和Coprococcus增加，而毛螺菌科和Allobaculum减少，这可能介导过量铁对肠道健康的有害影响。我们的结论是，过量的铁暴露于液态铁制剂诱导氧化应激和组织病理学改变的肠道和肝脏。肠屏障功能受损可增加铁转运，炎症沿着氧化应激增强肝脏铁沉积，可能导致进一步的肝损伤，形成恶性循环。这些影响伴随着较低的肠段损伤和改变肠道微生物组成的大鼠朝着一个档案与肠道疾病的风险增加。
The aim of this study was to determine the toxicological effects of excess iron in a liquid iron preparation (especially on intestinal barrier function) and the possible etiology of side effects or diseases caused by the excess iron. In study 1, forty male Sprague-Dawley rats (4-5 wk old) were subjected to oral gavage with 1 ml vehicle (0.01 mol/L HCl) or 1 ml liquid iron preparation containing 8 mg, 16 mg or 24 mg of iron for 30 d. Iron status, oxidative stress, histology (H&E staining), ultrastructure (electron microscopy) and apoptosis (TUNEL assay) in the intestines and liver were assessed. The cecal microbiota was evaluated by 16S rRNA sequencing. In study 2, twenty rats with the same profile as above were subjected to oral gavage with 1 ml vehicle or 24 mg Fe for 30 d. The intestinal barrier function was determined by in vivo studies and an Ussing chamber assay; tight junction proteins and serum pro-inflammatory cytokines were observed by enzyme-linked immunosorbent assay. In study 1, the intestinal mucosa and liver showed apparent oxidative stress. In addition, iron concentration-dependent ultrastructural alterations to duodenal enterocytes and hepatocytes and histological damage to the colonic mucosa were detected. Notably, apoptosis was increased in duodenal enterocytes and hepatocytes. Impaired intestinal barrier function and lower expression of intestinal tight junction proteins were observed, and the phenotype was more severe in the colon than in the duodenum. A trend toward higher expression of serum pro inflammatory cytokines might indicate systemic inflammation. Furthermore, the caecal microbiota showed a significant change, with increased Defluviitaleaceae, Ruminococcaceae, and Coprococcus and reduced Lachnospiraceae and Allobaculum, which could mediate the detrimental effects of excess iron on gut health. We concluded that excessive iron exposure from liquid iron preparation induces oxidative stress and histopathological alterations in the intestine and liver. Impaired intestinal barrier function could increase iron transportation, and inflammation along with oxidative stress-enhanced liver iron deposition may cause further liver injury in a vicious circle. These effects were accompanied by lower intestinal segment damage and altered gut microbial composition of rats toward a profile with an increased risk of gut disease.