Intestinal NEDD4L Signaling Inhibiting Carbon Tetrachloride-Induced Liver Fibrosis in Mice Involves Gut Lactobacillus Orchestrating Type 1 Interferon Expression

Abstract Liver fibrosis (LF), characterized by hepatic stellate cell (HSC) activation and linked to an imbalance of gut microbiota or organismal type 1 interferon (IFN1) at steady state, was demonstrated to be aggravated by the global deletion of neural precursor cell-expressed developmentally down-regulated 4-like ( Nedd4L ) in our previous work. To uncover the role of cell-type specific NEDD4L in LF and its relationship to the gut microbiota/IFN1 axis, intraperitoneal injection of carbon-tetrachloride (CCL4) was used to induce LF in adult female C57BL/6J mice with conditional knockout (cKO) of Nedd4L in hepatocytes, HSC or intestinal epithelial cells (IEC). Fibrotic mice were simultaneously treated with intragastric bacteria or intraperitoneal IFNα as needed. Results showed that Nedd4L cKO in IEC (not hepatocytes or HSC) significantly promoted LF, accompanied by marked reductions in the abundances of gut Lactobacillus , Desulfovibrio , Tyzzerella , Alistipes , Bacteroides and Colidexteribacter , and significantly decreased serum IFN1. Without the CCL4 challenge, Nedd4L cKO in IEC also reduced gut Lactobacillus , Bacteroides , Alistipes and serum IFN1. In mice with Nedd4L cKO in IEC, intragastric administration of Lactobacillus (not Bacteroides ) significantly attenuated LF, accompanied by significantly increased gut Lactobacillus , Bacteroides , Alloprevotella , Faecalibaculum and serum IFN1 level; however, Lactobacillus-mediated LF alleviation was antagonized upon deletion of the organismal IFN1 receptor. Finally, the LF degree could still be relieved by exogenous IFNα even when NEDD4L signaling in IEC was blocked. Overall, this study demonstrates that curbing CCL4-induced LF in C57BL/6J mice by endogenous IFN1 signaling requires intestinal NEDD4L signaling, which maintains the abundance of the gut genera Lactobacillus and thus facilitates endogenous IFN1 production.