Figure 4.

Role of gut microbiota-associated bile acids metabolism in liver injury and regeneration. After a liver injury or partial hepatectomy, bile acids (BAs) absorbed from the intestine suddenly become too high for the remnant liver, leading to secondary liver injury. Excessive BAs binding to hepatic farnesoid X receptor (FXR) inhibits transcription of cytochrome P450 family 7 subfamily A member 1 (CYP7A1), which reduces the production of primary BAs. In addition, activated FXR can promote the secretion of primary BAs into bile canaliculus and upregulate expression of Foxm1b, thus relieving BAs overload and facilitating liver regeneration. Meanwhile, in the small intestine, BAs activate intestinal FXR to secret fibroblast growth factor (FGF) 15/19, which binds to fibroblast growth factor receptor 4 (FGFR4). FGFR4/agonist also induces expression of Foxm1b and improves proliferation. Gut microbiota is responsible for secondary BAs production in the large intestine. Secondary BAs binding to intestinal transforming growth factor 5 (TGR5) elicits secretion of glucagon-like peptide 1 (GLP1), which activates the insulin signaling pathway. Absorbed secondary BAs binding to hepatic TGR5 has an anti-inflammatory effect by suppressing the release of TNF-α from the Kupffer cell. TGR5 activation also promotes BAs secretion by secreting ${\text{HCO}}_3^{-}$ and Cl^- from cholangiocyte and increasing transformation of hydrophilic BAs from hydrophobic BAs, which reduce BAs load and BAs toxicity-induced liver injury, promoting liver regeneration. Moreover, primary BAs stimulate and secondary BAs suppress the expression of chemokine (C-X-C motif) ligand 16 (CXCL16) by liver sinusoidal endothelial cells (LSECs). CXCL16 is a chemokine that recruits natural killer T (NKT) cells, which suppress liver tumors.