The deficiency of FKBP-5 inhibited hepatocellular progression by increasing the infiltration of distinct immune cells and inhibiting obesity-associated gut microbial metabolite

Gut microbiota has a number of essential roles in nutrition metabolism and immune homeostasis, and is closely related to hepatocellular progression. In recent years, studies have also shown that FK506 binding protein 5 (FKBP-5) plays a crucial role in immune regulation. However, it is not yet clear whether FKBP-5 promotes the development of hepatocellular carcinoma (HCC) by affecting immune function and gut microbiota.

Therefore, we demonstrated that FKBP-5 deletion inhibited hepatocellular progression by modulating immune response and gut microbiome-mediated BAs metabolism.

FKBP-5 expression was verified by immunochemistry and western blot and reverse transcription polymerase chain reaction (RT-qPCR) assays. After treatment in WT and FKBP-5-/- mice, the histological characteristic of mice liver tissue was assessed by H&E staining, and hepatic leukocytes and hepatic NKT cells were identified by flow cytometer. Meanwhile, primary bile acids (BAs), secondary BAs, serum total cholesterol, and the weight of abdomen adipose tissues were examined, and the gut microbiota was evaluated by 16S ribosomal ribonucleic acid (rRNA) sequencing.

We discovered that FKBP-5 was highly expressed in HCC tissues. Meanwhile, FKBP-5 deletion inhibited tumor progression by increasing CD8+ T, CD4+ T, NKT and CD4+NKT cells in mice after diethylnitrosamine (DEN) injection. Besides, we proved that FKBP-5 deletion generated rapid and significant reductions in the intestinal BAs, the weight of abdomen adipose tissues and the serum total cholesterol. FKBP-5 deletion also led to a change in the composition of gut microbiota, suggesting that BAs are the main dietary factor regulating gut microbiota, which could be affected by FKBP-5 deletion. Further, we uncovered that anti-CD4 and anti-CD8 treatments facilitated hepatocellular progression by modulating gut microbiota composition in FKBP-5-/- mice. Conclusions: Therefore, we demonstrated that FKBP-5 deletion inhibited hepatocellular progression by modulating immune response and gut microbiome-mediated BAs metabolism.