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

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 s...

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Main Authors: Schneider, Kai Markus (Author) , Mohs, Antje (Author) , Gui, Wenfang (Author) , Galvez, Eric J. C. (Author) , Candels, Lena Susanna (Author) , Hoenicke, Lisa (Author) , Muthukumarasamy, Uthayakumar (Author) , Holland, Christian H. (Author) , Elfers, Carsten (Author) , Kilic, Konrad (Author) , Schneider, Carolin Victoria (Author) , Schierwagen, Robert (Author) , Strnad, Pavel (Author) , Wirtz, Theresa H. (Author) , Marschall, Hanns-Ulrich (Author) , Latz, Eicke (Author) , Lelouvier, Benjamin (Author) , Sáez Rodríguez, Julio (Author) , de Vos, Willem (Author) , Strowig, Till (Author) , Trebicka, Jonel (Author) , Trautwein, Christian (Author)
Format: Article (Journal)
Language:English
Published: 08 July 2022
In: Nature Communications
Year: 2022, Volume: 13, Pages: 1-19
ISSN:2041-1723
DOI:10.1038/s41467-022-31312-5
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41467-022-31312-5
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41467-022-31312-5
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Author Notes: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 & Christian Trautwein
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Summary: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.
Item Description:Gesehen am 21.02.2023
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-022-31312-5

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