24-nor-ursodeoxycholic acid ameliorates inflammatory response and liver fibrosis in a murine model of hepatic Schistosomiasis

Background & Aims Intrahepatic granuloma formation and fibrosis characterize the pathological features of Schistosoma mansoni infection. Based on previously observed substantial anti-fibrotic effects of 24- nor -ursodeoxycholic acid ( nor UDCA) in Abcb4/Mdr2 −/− mice with cholestatic liver injury and biliary fibrosis, we hypothesized that nor UDCA improves inflammation-driven liver fibrosis in S. mansoni infection. Methods Adult NMRI mice were infected with 50 S. mansoni cercariae and after 12weeks received either nor UDCA- or ursodeoxycholic acid (UDCA)-enriched diet (0.5% wt/wt) for 4weeks. Bile acid effects on liver histology, serum biochemistry, key regulatory cytokines, hepatic hydroxyproline content as well as granuloma formation were compared to naive mice and infected controls. In addition, effects of nor UDCA on primary T-cell activation/proliferation and maturation of the antigen-presenting-cells (dendritic cells, macrophages) were determined in vitro . Results UDCA as well as nor UDCA attenuated the inflammatory response in livers of S. mansoni infected mice, but exclusively nor UDCA changed cellular composition and reduced size of hepatic granulomas as well as TH2-mediated hepatic fibrosis in vivo . Moreover, nor UDCA affected surface expression level of major histocompatibility complex (MHC) class II of macrophages and dendritic cells as well as activation/proliferation of T-lymphocytes in vitro , whereas UDCA had no effect. Conclusions This study demonstrates pronounced anti-inflammatory and anti-fibrotic effects of nor UDCA compared to UDCA in S. mansoni induced liver injury, and indicates that nor UDCA directly represses antigen presentation of antigen presenting cells and subsequent T-cell activation in vitro . Therefore, nor UDCA represents a promising drug for the treatment of this important cause of liver fibrosis.