Journal Article

Colitis ameliorates cholestatic liver disease via suppression of bile acid synthesis

Gaßler, Nikolaus, Schneider, Kai Markus, Muthukumarasamy, Uthayakumar, Su, Huan, Liao, Lijun, Hole, Mikal Jacob, Edlund, Karolina, Mohs, Antje, Marschall, Hanns-Ulrich, Gui, Wenfang, Schneider, Carolin V., Hengstler, Jan G., Jørgensen, Kristin K., Jaeger, Julius, Begher-Tibbe, Brigitte, Strowig, Till, Hov, Johannes R., Mertens, Christian J., Trautwein, Christian, Molinaro, Antonio, Bergheim, Ina

2023

Overview

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by chronic inflammation and progressive fibrosis of the biliary tree. The majority of PSC patients suffer from concomitant inflammatory bowel disease (IBD), which has been suggested to promote disease development and progression. However, the molecular mechanisms by which intestinal inflammation may aggravate cholestatic liver disease remain incompletely understood. Here, we employ an IBD-PSC mouse model to investigate the impact of colitis on bile acid metabolism and cholestatic liver injury. Unexpectedly, intestinal inflammation and barrier impairment improve acute cholestatic liver injury and result in reduced liver fibrosis in a chronic colitis model. This phenotype is independent of colitis-induced alterations of microbial bile acid metabolism but mediated via hepatocellular NF-κB activation by lipopolysaccharide (LPS), which suppresses bile acid metabolism in-vitro and in-vivo. This study identifies a colitis-triggered protective circuit suppressing cholestatic liver disease and encourages multi-organ treatment strategies for PSC. The association between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) has been known for decades, but mechanisms of gut-liver crosstalk are incompletely understood. Here, the authors show a colitis-triggered protective circuit suppressing cholestatic liver disease which encourages multi-organ treatment strategies for PSC.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45/88 / 49/91 / 631/80/304 / 64/60 / 692/4020/4021/1328/1325/2744 / 692/699/1503/257/1389 / 82/1 / 82/29 / 82/51 / 82/80 / 96/2 / 96/31 / 96/63 / Acids / Animals / Bile / Bile Acids and Salts / Cell and Molecular Biology / Cell- och molekylärbiologi / Cholangitis / Cholangitis, Sclerosing - complications / Cholangitis, Sclerosing - therapy / Cholestasis - complications / Circuits / Colitis / Colitis - complications / Fibrosis / Humanities and Social Sciences / Inflammation / Inflammation - complications / Inflammatory bowel disease / Inflammatory bowel diseases / Inflammatory Bowel Diseases - complications / Injury prevention / Intestine / Lipopolysaccharides / Liver / Liver Diseases / Metabolism / Mice / Microorganisms / Molecular modelling / multidisciplinary / NF-κB protein / Phenotypes / Science / Science (multidisciplinary)