Oral delivery of a Lactococcus lactis expressing extracellular TGFßR2 alleviates hepatic fibrosis.

ABSTRACT

Liver fibrosis is caused by the accumulation of extracellular matrix proteins on the surface of hepatocytes and results from chronic liver injury. TGFß1 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 TGFß1 binds to TGFßR2 to mediate its downstream signal cascades to regulate target gene transcription. Therefore, the TGFßR2 blocker might be a prominent drug candidate. We constructed TGFßR2 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 TGFß1-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 TGFßR2 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.