College of Animal Science, South China Agricultural University/Guangdong Laboratory for Lingnan Modern Agriculture/Guangdong Provincial Key Laboratory of Animal Nutrition Control/National Engineering Research Center for Breeding Swine Industry, Guangzhou, People's Republic of China.
Integrative Microbiology Research Centre, South China Agricultural University, Guangzhou, People's Republic of China.
Stem Cells. 2021 Apr;39(4):482-496. doi: 10.1002/stem.3324. Epub 2021 Jan 3.
Enterotoxigenic Escherichia coli causes severe infectious diarrhea with high morbidity and mortality in newborn and weanling pigs mainly through the production of heat-stable enterotoxins (STs). However, the precise regulatory mechanisms involved in ST-induced intestinal epithelium injury remain unclear. Consequently, we conducted the experiments in vivo (mice), ex vivo (mouse and porcine enteroids), and in vitro (MODE-K and IPEC-J2 cells) to explore the effect of STp (one type of STa) on the integrity of the intestinal epithelium. The results showed that acute STp exposure led to small intestinal edema, disrupted intestinal integrity, induced crypt cell expansion into spheroids, and downregulated Wnt/β-catenin activity in the mice. Following a similar trend, the enteroid-budding efficiency and the expression of Active β-catenin, β-catenin, Lgr5, PCNA, and KRT20 were significantly decreased after STp treatment, as determined ex vivo. In addition, STp inhibited cell proliferation, induced cell apoptosis, destroyed cell barriers, and reduced Wnt/β-catenin activity by downregulating its membrane receptor Frizzled7 (FZD7). In contrast, Wnt/β-catenin reactivation protected the IPEC-J2 cells from STp-induced injury. Taking these findings together, we conclude that STp inhibits intestinal stem cell expansion to disrupt the integrity of the intestinal mucosa through the downregulation of the Wnt/β-catenin signaling pathway.
产肠毒素性大肠杆菌（Enterotoxigenic Escherichia coli）主要通过产生热稳定肠毒素（STs）引起新生仔猪和断奶仔猪严重的感染性腹泻，发病率和死亡率高。然而，ST 诱导的肠上皮损伤涉及的确切调节机制仍不清楚。因此，我们在体内（小鼠）、体外（鼠和猪类器官）和体外（MODE-K 和 IPEC-J2 细胞）进行实验，以研究 STp（一种 STa）对肠上皮完整性的影响。结果表明，急性 STp 暴露导致小肠水肿、破坏肠完整性、诱导隐窝细胞扩张成球体，并下调小鼠的 Wnt/β-catenin 活性。类似的趋势是，类器官出芽效率和 Active β-catenin、β-catenin、Lgr5、PCNA 和 KRT20 的表达在 STp 处理后明显下降，这是在体外观察到的。此外，STp 通过下调其膜受体 Frizzled7（FZD7）抑制细胞增殖、诱导细胞凋亡、破坏细胞屏障和降低 Wnt/β-catenin 活性。相比之下，Wnt/β-catenin 再激活可保护 IPEC-J2 细胞免受 STp 诱导的损伤。综合这些发现，我们得出结论，STp 通过下调 Wnt/β-catenin 信号通路抑制肠干细胞扩张，破坏肠黏膜的完整性。
