Imbalanced gut microbiota fuels hepatocellular carcinoma development by shaping the hepatic inflammatory microenvironment

Kai Markus Schneider, Antje Mohs, Wenfang Gui, Eric J. C. Galvez, Lena Susanna Candels, Lisa Hoenicke, Uthayakumar Muthukumarasamy, Christian H. Holland, Carsten Elfers, Konrad Kilic, Carolin Victoria Schneider, Robert Schierwagen, Pavel Strnad, Theresa H. Wirtz, Hanns-Ulrich Marschall, Eicke Latz, Benjamin Lelouvier, Julio Saez-Rodriguez, Willem de Vos, Till Strowig, Jonel Trebicka and Christian Trautwein ()
Additional contact information
Kai Markus Schneider: University Hospital RWTH Aachen
Antje Mohs: University Hospital RWTH Aachen
Wenfang Gui: University Hospital RWTH Aachen
Eric J. C. Galvez: Germany and Hannover Medical School
Lena Susanna Candels: University Hospital RWTH Aachen
Lisa Hoenicke: Germany and Hannover Medical School
Uthayakumar Muthukumarasamy: Germany and Hannover Medical School
Christian H. Holland: Faculty of Medicine, and Heidelberg University Hospital
Carsten Elfers: University Hospital RWTH Aachen
Konrad Kilic: University Hospital RWTH Aachen
Carolin Victoria Schneider: University Hospital RWTH Aachen
Robert Schierwagen: European Foundation for the Study of Chronic Liver Failure (EF-CLIF)
Pavel Strnad: University Hospital RWTH Aachen
Theresa H. Wirtz: University Hospital RWTH Aachen
Hanns-Ulrich Marschall: University of Gothenburg
Eicke Latz: University of Bonn
Benjamin Lelouvier: Vaiomer SAS
Julio Saez-Rodriguez: Faculty of Medicine, and Heidelberg University Hospital
Willem de Vos: Wageningen University
Till Strowig: Germany and Hannover Medical School
Jonel Trebicka: European Foundation for the Study of Chronic Liver Failure (EF-CLIF)
Christian Trautwein: University Hospital RWTH Aachen

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31312-5

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