Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria
Moritz Meyer
Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria
Daniel Steinacher
Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
Thierry Claudel
Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
Bela Hausmann
Joint Microbiome Facility of the Medical University of Vienna, The University of Vienna, Vienna, Austria; Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
Petra Pjevac
Joint Microbiome Facility of the Medical University of Vienna, The University of Vienna, Vienna, Austria; Division of Microbial Ecology, Department of Microbiology and Ecosystem Science, Centre for Microbiology and Environmental Systems Science, University of Vienna, Vienna, Austria
Felix Grabherr
Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria
Georg Oberhuber
INNPATH, Tirol-Kliniken University Hospital Innsbruck, Innsbruck, Austria
Manuel Grander
Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University Innsbruck, Innsbruck, Austria
Natascha Brigo
Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University Innsbruck, Innsbruck, Austria
Almina Jukic
Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria
Julian Schwärzler
Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria
Günter Weiss
Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University Innsbruck, Innsbruck, Austria
Timon E. Adolph
Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria
Michael Trauner
Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; Corresponding authors. Addresses: Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria. Tel.: +43-512-504-23539; Fax: +43-512-504-23538 (H. Tilg); Department of Medicine III, Medical University of Vienna, Vienna, Austria. Tel.: +43-(0)14040047440; Fax: +43-(0)14040047350 (M. Trauner)
Herbert Tilg
Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria; Corresponding authors. Addresses: Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria. Tel.: +43-512-504-23539; Fax: +43-512-504-23538 (H. Tilg); Department of Medicine III, Medical University of Vienna, Vienna, Austria. Tel.: +43-(0)14040047440; Fax: +43-(0)14040047350 (M. Trauner)
Background & Aims: Alcohol-related liver disease (ALD) is a global healthcare challenge with limited treatment options. 24-Norursodeoxycholic acid (NorUDCA) is a synthetic bile acid with anti-inflammatory properties in experimental and human cholestatic liver diseases. In the present study, we explored the efficacy of norUDCA in experimental ALD. Methods: NorUDCA was tested in a preventive and therapeutic setting in an experimental ALD model (Lieber–DeCarli diet enriched with ethanol). Liver disease was phenotypically evaluated using histology and biochemical methods, and anti-inflammatory properties and peroxisome proliferator-activated receptor gamma activation by norUDCA were evaluated in cellular model systems. Results: NorUDCA administration ameliorated ethanol-induced liver injury, reduced hepatocyte death, and reduced the expression of hepatic pro-inflammatory cytokines including tumour necrosis factor (Tnf), Il-1β, Il-6, and Il-10. NorUDCA shifted hepatic macrophages towards an anti-inflammatory M2 phenotype. Further, norUDCA administration altered the composition of the intestinal microbiota, specifically increasing the abundance of Roseburia, Enterobacteriaceae, and Clostridum spp. In a therapeutic model, norUDCA also ameliorated ethanol-induced liver injury. Moreover, norUDCA suppressed lipopolysaccharide-induced IL-6 expression in human peripheral blood mononuclear cells and evoked peroxisome proliferator-activated receptor gamma activation. Conclusions: NorUDCA ameliorated experimental ALD, protected against hepatic inflammation, and affected gut microbial commensalism. NorUDCA could serve as a novel therapeutic agent in the future management of patients with ALD. Impact and implications: Alcohol-related liver disease is a global healthcare concern with limited treatment options. 24-Norursodeoxycholic acid (NorUDCA) is a modified bile acid, which was proven to be effective in human cholestatic liver diseases. In the present study, we found a protective effect of norUDCA in experimental alcoholic liver disease. For patients with ALD, norUDCA could be a potential new treatment option.
