Zinc L-Aspartate enhances intestinal stem cell activity to protect the integrity of the intestinal mucosa against deoxynivalenol through activation of the Wnt/β-catenin signaling pathway
Zinc L-Aspartate enhances intestinal stem cell activity to protect the integrity of the intestinal mucosa against deoxynivalenol through activation of the Wnt/β-catenin signaling pathway
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L-天门冬氨酸锌通过激活 Wnt/β-连环蛋白信号通路增强肠道干细胞活性，保护肠粘膜的完整性，免受脱氧雪腐镰刀菌烯醇的侵害
DOI：
10.1016/j.envpol.2020.114290
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发表时间：
2020
影响因子：
8.9
通讯作者：
Xiu-qi Wang
中科院分区：
文献类型：
--
作者：
Jia-yi Zhou;Hua-lin Lin;Zhe Wang;Sai-wu Zhang;Deng-gui Huang;Chun-qi Gao;Hui-chao Yan;Xiu-qi Wang
微量营养素锌在调节细胞信号识别和增强肠道屏障功能方面起着至关重要的作用。然而，在生理和病理条件下，锌调节肠干细胞（ISC）更新和再生能力，驱动肠上皮更新以维持肠屏障的确切机制尚不清楚。本研究采用小鼠plusex vivoenteroid模型，研究L-天冬氨酸锌（Zn-Asp）对脱氧雪腐镰刀菌烯醇（DON）诱导的肠粘膜损伤的保护作用。结果表明，与20 mg/kg体重相比，10 mg/kg体重的Zn-Asp（以锌计算）显著增加了空肠重量，改善了DON引起的空肠粘膜损伤，包括改善了肠的形态和屏障，以及肠样组织的形成和出芽效率。Zn-Asp刺激的修复过程还伴随着KRT 20和Villin的荧光信号强度增加;小鼠空肠中MUC 2+、CAG+、LYZ+、BrdU+和Ki 67+细胞的数量增加;以及空肠、隐窝和肠样组织中Ki 67和PCNA的蛋白表达。同时，Zn-Asp增加ISC活性，促进肠上皮更新，即使在生理条件下。在离体肠上皮细胞培养实验中，用100 μmol/L Zn-Asp（以锌计算）和100 ng/mL DON处理72 h，进一步验证了上述结果。此外，我们证明Zn-Asp改善肠道完整性或加速伤口愈合沿着Wnt/β-catenin信号上调或再激活。提示Zn-Asp，尤其是Zn，通过激活Wnt/β-catenin信号通路，增强ISC活性，维持肠道完整性，这为在药物、保健食品或合格饲料中添加外源性锌制剂，以ISC为基础，有效预防真菌毒素所致肠道损伤提供了一定的理论依据。
The micronutrient, zinc, plays a vital role in modulating cellular signaling recognition and enhancing intestinal barrier function. However, the precise mechanisms underlying the zinc regulation of intestinal stem cell (ISC) renewal and regeneration ability, which drive intestinal epithelial turnover to maintain the intestinal barrier, under physiological and pathological conditions are unknown. In this study, we usedin vivomouse plusex vivoenteroid model to investigate thoroughly the protection efficacy of zinc L-aspartate (Zn-Asp) on intestinal mucosal integrity exposed to deoxynivalenol (DON). The results showed that 10 rather than 20 mg/kg body weight (BW) Zn-Asp (calculation in zinc) significantly increased the jejunum mass and ameliorated mucosa injury caused by 2 mg/kg BW DON treatment, including improvement of the intestinal morphology and barrier, as well as enteroid-forming and -budding efficiency, which was expanded from crypt cells isolated from jejunum of mice in each group. The repair process stimulated by Zn-Asp was also accompanied by increased fluorescence signal intensity of KRT20 and Villin; increased numbers of MUC2+, CAG+, LYZ+, BrdU+and Ki67+cells in mouse jejunum; and protein expression of Ki67 and PCNA in the jejunum, crypt and enteroid. Simultaneously, Zn-Asp increased ISC activity to promote intestinal epithelial renewal even under physiological conditions. These results were further verified in ex vivoenteroid culture experiments, which were treated with 100 μmol/L Zn-Asp (calculation in zinc) and 100 ng/mL DON for 72 h. Furthermore, we demonstrated that Zn-Asp improved intestinal integrity or accelerated wound healing along with Wnt/β-catenin signaling upregulation or reactivation. Our findings indicate Zn-Asp, especially Zn, enhances ISC activity to maintain the intestinal integrity by activating the Wnt/β-catenin signaling, which sheds some light upon effective preventive strategies for intestinal injury induced by mycotoxin based on ISCs with exogenous zinc preparations in the proper drugs, health foods or qualified feed.