Oral delivery of a Lactococcus lactis expressing extracellular TGF beta R2 alleviates hepatic fibrosis
Oral delivery of a Lactococcus lactis expressing extracellular TGF beta R2 alleviates hepatic fibrosis
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口服表达细胞外 TGF beta R2 的乳酸乳球菌可减轻肝纤维化
DOI：
10.1007/s00253-021-11485-7
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发表时间：
2021
影响因子：
5
通讯作者：
Jin Wanzhu
中科院分区：
文献类型：
--
作者：
Yuan Shouli;Dong Meng;Zhang Hanlin;Xu Hongde;Wang Qi;Yan Chunlong;Ye Rongcai;Jiang Xiaoxiao;Zhou Huiqiao;Chen Li;Cheng Jun;Xie Wen;Jin Wanzhu
肝纤维化是由细胞外基质蛋白在肝细胞表面积聚引起的，是慢性肝损伤的结果。TGFβ1是肝纤维化最重要的促进因子之一，它加速了肝星状细胞向肌成纤维细胞的转化和胶原的表达。众所周知，TGFβ1与TGFβR2结合，介导其下游信号级联，从而调节靶基因的转录。因此，TGFβR2阻断剂可能是一个突出的候选药物。本研究将转化生长因子β受体2（TGFβR2）胞外区构建到生物治疗活性乳酸乳球菌中，以减轻四氯化碳（CCl 4）处理的小鼠肝纤维化。结果表明，重组菌培养上清能在细胞水平上抑制TGFβ1诱导的肝星状细胞胶原合成。此外，体内研究结果表明，重组细菌显着降低CCl4处理小鼠的肝纤维化程度。流式细胞仪检测结果显示，重组菌处理组与空载体菌组相比，CD11b+Kupffer细胞明显减少。结果表明，重组细菌处理后，纤维化相关基因和蛋白表达显著降低。最后，亚慢性毒性试验结果表明，该菌株没有任何明显的副作用。结论：重组乳酸乳球菌对肝纤维化有很好的治疗作用。表达TGFβR2的乳酸抑制肌成纤维细胞的活化。口服重组菌株降低了小鼠的肝纤维化和炎症程度。·小鼠亚慢性毒性试验表明，重组菌是安全的。
Liver fibrosis is caused by the accumulation of extracellular matrix proteins on the surface of hepatocytes and results from chronic liver injury. TGFβ1 is one of the most important promoters of hepatic fibrosis, which accelerates the transformation of hepatic stellate cells to myofibroblasts and collagen expression. It is well-known that TGFβ1 binds to TGFβR2 to mediate its downstream signal cascades to regulate target gene transcription. Therefore, the TGFβR2 blocker might be a prominent drug candidate. We constructed TGFβR2 extracellular domain into living biotherapeuticsLactococcus lactisto reduce hepatic fibrosis in CCl4treated mice in the present study. We found that the culture supernatant of the recombinant bacteria can inhibit the TGFβ1-induced collagen synthesis in the hepatic stellate cells at the cellular level. In addition, results of in vivo study showed that the recombinant bacteria significantly reduced the degree of liver fibrosis in CCl4-treated mice. Furthermore, flow cytometry results indicated that the recombinant bacteria treatment significantly reduced the CD11b+Kupffer cells compared with the empty vector bacteria group. Consistently, fibrosis-related gene and protein expression were significantly reduced upon recombinant bacteria treatment. Finally, the subchronic toxicity test results showed that this bacteria strain did not have any significant side effects. In conclusion, our recombinantLactococcus lactisshows tremendous therapeutic potential in liver fibrosis.Key points•The supernatant of L. lactis expressing TGFβR2 inhibits the activation of myofibroblast.•The oral recombinant strain reduced the degree of liver fibrosis and inflammation in mice.•The recombinant strain was safe in subchronic toxicity test in mice.