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The Th2 cytokine IL-13 is involved in biliary epithelial injury and liver fibrosis in patients as well as in animal models. The aim of this study was to investigate IL-13 as a therapeutic target during short term and chronic intrahepatic cholestasis in an <i>Abcb4-</i>knockout mouse model (<i>Abcb4</i>^−/−). Lack of IL-13 protected <i>Abcb4</i>^−/− mice transiently from cholestasis. This decrease in serum bile acids was accompanied by an enhanced excretion of bile acids and a normalization of fecal bile acid composition. In <i>Abcb4^−/−/IL-13</i>^−/− double knockout mice, bacterial translocation to the liver was significantly reduced and the intestinal microbiome resembled the commensal composition in wild type animals. In addition, 52-week-old <i>Abcb4^−/−IL-13</i>^−/− mice showed significantly reduced hepatic fibrosis. <i>Abcb4</i>^−/− mice devoid of IL-13 transiently improved cholestasis and converted the composition of the gut microbiota towards healthy conditions. This highlights IL-13 as a potential therapeutic target in biliary diseases.