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Abstract Details
Imbalanced gut microbiota fuels hepatocellular carcinoma development by shaping the hepatic inflammatory microenvironment
1Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
2Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
3Helmholtz Centre for Infection Research, Braunschweig, Germany and Hannover Medical School, Hannover, Germany.
4Institute for Computational Biomedicine, Bioquant, Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Heidelberg, Germany.
5Joint Research Centre for Computational Biomedicine (JRC-COMBINE), RWTH Aachen University, Faculty of Medicine, Aachen, Germany.
6The Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
7European Foundation for the Study of Chronic Liver Failure (EF-CLIF), 08021, Barcelona, Spain.
8Translational Hepatology, Department of Internal Medicine I, Goethe University Frankfurt, 60323, Frankfurt, Germany.
9Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
10Institute of Innate Immunity, Medical Faculty, University of Bonn, 53127, Bonn, Germany.
11Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, 01655, USA.
12German Center for Neurodegenerative Diseases, 53127, Bonn, Germany.
13Vaiomer SAS, Labège, France.
14Laboratory of Microbiology, Wageningen University, 6708 WE, Wageningen, The Netherlands.
15Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, P.O. Box 63, 00014, Helsinki, Finland.
16Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany. ctrautwein@ukaachen.de.
#Contributed equally.
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, and therapeutic options for advanced HCC are limited. Here, we observe that intestinal dysbiosis affects antitumor immune surveillance and drives liver disease progression towards cancer. Dysbiotic microbiota, as seen in Nlrp6-/- mice, induces a Toll-like receptor 4 dependent expansion of hepatic monocytic myeloid-derived suppressor cells (mMDSC) and suppression of T-cell abundance. This phenotype is transmissible via fecal microbiota transfer and reversible upon antibiotic treatment, pointing to the high plasticity of the tumor microenvironment. While loss of Akkermansia muciniphila correlates with mMDSC abundance, its reintroduction restores intestinal barrier function and strongly reduces liver inflammation and fibrosis. Cirrhosis patients display increased bacterial abundance in hepatic tissue, which induces pronounced transcriptional changes, including activation of fibro-inflammatory pathways as well as circuits mediating cancer immunosuppression. This study demonstrates that gut microbiota closely shapes the hepatic inflammatory microenvironment opening approaches for cancer prevention and therapy.