Abstract
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 biotherapeutics Lactococcus lactis to reduce hepatic fibrosis in CCl4 treated 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 recombinant Lactococcus lactis shows 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.
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Acknowledgements
We thank Huiru Lian (University College London, London, UK) for revising the language of the manuscript.
Funding
This work was supported by the General Program (Major Research Plan) of the National Natural Science Foundation of China (92057208), the National Key Research and Development Program of China (2017YFC1001003), and the National Natural Science Foundation of China (81770834).
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W. Z. J. designed experiments, analyzed the data, and revised the manuscript. W. X. and J. C. revised the manuscript. S. L. Y. performed experiments, analyzed the data, and wrote the manuscript. M. D. and H. L. Z performed experiments, analyzed the data, and revised the manuscript. Q. W. analyzed the data. H. D. X and C. L. Y. performed experiments. Other authors helped with the experiments. All authors read and approved the manuscript.
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W. Z. J. filed a patent on this study.
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Yuan, S., Dong, M., Zhang, H. et al. Oral delivery of a Lactococcus lactis expressing extracellular TGFβR2 alleviates hepatic fibrosis. Appl Microbiol Biotechnol 105, 6007–6018 (2021). https://doi.org/10.1007/s00253-021-11485-7
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DOI: https://doi.org/10.1007/s00253-021-11485-7