The role of gut microbiota in liver regeneration

Abstract

The liver has unique regeneration potential, which ensures the continuous dependence of the human body on hepatic functions. As the composition and function of gut microbiota has been gradually elucidated, the vital role of gut microbiota in liver regeneration through gut-liver axis has recently been accepted. In the process of liver regeneration, gut microbiota composition is changed. Moreover, gut microbiota can contribute to the regulation of the liver immune microenvironment, thereby modulating the release of inflammatory factors including IL-6, TNF-α, HGF, IFN-γ and TGF-β, which involve in different phases of liver regeneration. And previous research have demonstrated that through enterohepatic circulation, bile acids (BAs), lipopolysaccharide, short-chain fatty acids and other metabolites of gut microbiota associate with liver and may promote liver regeneration through various pathways. In this perspective, by summarizing gut microbiota-derived signaling pathways that promote liver regeneration, we unveil the role of gut microbiota in liver regeneration and provide feasible strategies to promote liver regeneration by altering gut microbiota composition.

Keywords: gut microbiota; inflammatory cytokines; liver regeneration; microbial metabolic activity; regulate gut microbiota.

Figure 1

Factors that play a role in process of liver regeneration. IL-6 and TNF-α induce the priming phase. Complete mitogens including HGF, EGF, HB-EGF and TGF-α, together with auxiliary mitogens BAs, norepinephrine, TNF, IL-6, vascular endothelial growth factor, insulin-like growth factor system, estrogen, serotonin, leptin, complement, FGF1 and FGF2 involve in the proliferation phase. And the termination phase is induced by TGF-β. NE, norepinephrine, VEGF, vascular endothelial growth factor, IGF, insulin-like growth factor.

Figure 2

The role of gut microbiota in BAs related negative and positive regulation pathways of liver regeneration. FGF19 inhibit the rate-limiting enzyme for the synthesis of BAs, CYP7a1 and thus down-regulate BAs synthesis. And there is a positive feedback regulation of FGF19 by acting on FGFR on hepatocytes. BAs released into the intestine by the gallbladder act on FXR on intestinal epithelial cells and induce the release of FGF19 and FGF19. Then FGF19 reach liver through portal vein and function in the same way. FGF15 bond with FGFR4 to increase SHP1 expression in hepatocytes and decrease the level of CYP7a1 and CYP8b1. Secondary BAs converted from primary BAs by gut microbiota can inhibit FXR and activate TGR5, secreting inflammatory cytokines. These cytokines can be collected by portal vein and function to delay liver regeneration. The activation of TGR5 can also increase the bile secretion and mobility to reduce BAs overload in liver.

Figure 3

Gut-derived LPS translocates by chylomicrons and increase intestine permeability to promote liver regeneration. LPS induce the release of IL-6 and TNF-α in Kupffer cells through NF-κB signaling pathway. IL-6 promote the DNA synthesis and mitosis of hepatocytes by activating JAK/STAT pathway and Ras-Raf-MAPK pathway. IL-6 promote the DNA synthesis and mitosis of hepatocytes by activating JAK/STAT pathway and Ras-Raf-MAPK pathway. TNF-α activate JNK and MAPK-ERK, inducing cyclin D1 expression. Besides, LPS can enhance the effect of HGF on hepatocytes.