Faculty of Medicine, Department of Microbiology, Chulalongkorn University, Bangkok, Thailand.
Medical Microbiology, Interdisciplinary Program, Graduate School, Chulalongkorn University, Bangkok, Thailand.
Am J Physiol Gastrointest Liver Physiol. 2020 May 1;318(5):G966-G979. doi: 10.1152/ajpgi.00337.2019. Epub 2020 Apr 20.
Iron overload induces intestinal-permeability defect (gut leakage), and gut translocation of organismal molecules might enhance systemic inflammation and sepsis severity in patients with thalassemia (Thal). Hence, iron administration in Hbb mice, heterozygous β-globin-deficient Thal mice, was explored. Oral iron administration induced more severe secondary hemochromatosis and gut leakage in Thal mice compared with wild-type (WT) mice. Gut leakage was determined by ) FITC-dextran assay, ) spontaneous serum elevation of endotoxin (LPS) and (1→3)-β-d-glucan (BG), molecular structures of gut-organisms, and ) reduction of tight-junction molecules with increased enterocyte apoptosis (activated caspase-3) by immunofluorescent staining. Iron overload also enhanced serum cytokines and increased spp. (gram-negative bacteria) in feces as analyzed by microbiome analysis. LPS injection in iron-overloaded Thal mice produced higher mortality and prominent cytokine responses. Additionally, stimulation with LPS plus iron in macrophage from Thal mice induced higher cytokines production with lower β-globin gene expression compared with WT. Furthermore, possible gut leakage as determined by elevated LPS or BG (>60 pg/mL) in serum without systemic infection was demonstrated in 18 out of 41 patients with β-thalassemia major. Finally, enhanced LPS-induced cytokine responses of mononuclear cells from these patients compared with cells from healthy volunteers were demonstrated. In conclusion, oral iron administration in Thal mice induced more severe gut leakage and increased fecal gram-negative bacteria, resulting in higher levels of endotoxemia and serum inflammatory cytokines compared with WT. Preexisting hyperinflammatory cytokines in iron-overloaded Thal enhanced susceptibility toward infection. Although the impact of iron accumulation in several organs of patients with thalassemia is well known, the adverse effect of iron accumulation in gut is not frequently mentioned. Here, we demonstrated iron-induced gut-permeability defect, impact of organismal molecules from gut translocation of, and macrophage functional defect upon the increased sepsis susceptibility in thalassemia mice.
铁过载可诱导肠道通透性缺陷（肠漏），机体分子的肠道易位可能会增强地中海贫血（Thal）患者的全身炎症和败血症的严重程度。因此，研究人员在杂合子β-球蛋白缺陷的 Thal 小鼠（Hbb 小鼠）中探索了铁的给药途径。与野生型（WT）小鼠相比，口服铁给药在 Thal 小鼠中引起更严重的继发性血色素沉着症和肠漏。通过 FITC-葡聚糖测定法、内毒素（LPS）和（1→3）-β-D-葡聚糖（BG）的自发性血清升高、肠道器官的分子结构以及紧密连接分子的减少和肠上皮细胞凋亡（激活的 caspase-3）的免疫荧光染色来确定肠漏。铁过载还增强了血清细胞因子，并增加了粪便中的 spp.（革兰氏阴性菌），通过微生物组分析进行分析。在铁过载的 Thal 小鼠中注射 LPS 会导致更高的死亡率和更明显的细胞因子反应。此外，与 WT 相比，用 LPS 和铁刺激 Thal 小鼠的巨噬细胞会诱导更高的细胞因子产生和更低的β-球蛋白基因表达。此外，在 41 名β-地中海贫血患者中，有 18 名患者的血清中没有全身感染，但出现了 LPS 或 BG（>60pg/mL）升高，表明可能存在肠漏。最后，与健康志愿者的细胞相比，这些患者的单核细胞中 LPS 诱导的细胞因子反应增强。总之，与 WT 相比，铁过载的 Thal 小鼠口服铁给药后会引起更严重的肠漏和粪便中革兰氏阴性菌增加，导致内毒素血症和血清炎症细胞因子水平升高。铁过载的 Thal 中预先存在的过度炎症细胞因子增强了对感染的易感性。尽管人们已经很清楚铁在铁过载患者的多个器官中的积累的影响，但铁在肠道中的积累的不良影响并不经常被提及。在这里，我们证明了铁诱导的肠道通透性缺陷、肠道易位的机体分子的影响以及铁过载时巨噬细胞功能缺陷导致 Thal 小鼠败血症易感性增加。
