IL-13 as Target to Reduce Cholestasis and Dysbiosis in Abcb4 Knockout Mice

Abstract

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 Abcb4-knockout mouse model (Abcb4−/−). Lack of IL-13 protected Abcb4−/− 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 Abcb4−/−/IL-13−/− 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 Abcb4−/−IL-13−/− mice showed significantly reduced hepatic fibrosis. Abcb4−/− 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.

Interleukin-13 (IL-13)—A Pleiotropic Cytokine Involved in Wound Healing and Fibrosis

“…IL-13 also plays an essential role in the pathophysiology of ulcerative colitis [ 50 ]. It is known that IL-13 can disrupt intestinal barrier function by inducing apoptosis and altering the protein composition of tight junctions [ 34 , 51 ]. The activation of the IL-13 receptor a1 by IL-13 increased claudin-2 expression and thus directly or indirectly enhanced intestinal barrier disruption [ 51 ].…”

“…The mechanistic effects of IL-13 on energy metabolism at the cellular and molecular level need further evaluation. On the other hand, IL-13 was associated with biliary fibrosis, diarrhea, and perianal inflammation in a genetic model of cholestasis, ABCB4-knockout mice [ 34 ]. These results seem to be contradictory or at least need clarification.…”

Special Issue on “Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis II”

“…In this regard, Hahn et al investigated the cytokine IL-13 as a therapeutic target during short term and chronic intrahepatic cholestasis in an Abcb4 -knockout mouse model, which is a spontaneous model resembling PSC, and further in an Abcb4 −/− / Il-13 −/− double knockout model [ 22 ]. The authors could demonstrate that the loss of IL-13 transiently improves cholestasis and is associated with profound beneficial compositional changes in gut microbiota, as well as the normalization of serum and fecal bile acid composition.…”

“…The authors could demonstrate that the loss of IL-13 transiently improves cholestasis and is associated with profound beneficial compositional changes in gut microbiota, as well as the normalization of serum and fecal bile acid composition. The authors, therefore, suggested that targeting Il-13 expression might be an effective therapeutic means to improve bile duct disorders [ 22 ].…”

Immunopathobiology and therapeutic targets related to cytokines in liver diseases

“…72 The pathogenic mechanisms of Th2 cytokines in biliary diseases have been further elucidated in recent papers. 73,74 Mice deficient in the Mdr2 gene have been used as a common model of PSC due to their defective secretion of phospholipids into bile. PSC accelerates the proliferation of cholangiocytes and subsequent ductular reaction, fibrosis and biliary cirrhosis.…”