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

Author

Listed:
  • Kai Markus Schneider

    (University Hospital RWTH Aachen
    University of Pennsylvania)

  • 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
    Faculty of Medicine)

  • Carsten Elfers

    (University Hospital RWTH Aachen)

  • Konrad Kilic

    (University Hospital RWTH Aachen)

  • Carolin Victoria Schneider

    (University Hospital RWTH Aachen
    University of Pennsylvania)

  • Robert Schierwagen

    (European Foundation for the Study of Chronic Liver Failure (EF-CLIF)
    Goethe University Frankfurt)

  • Pavel Strnad

    (University Hospital RWTH Aachen)

  • Theresa H. Wirtz

    (University Hospital RWTH Aachen)

  • Hanns-Ulrich Marschall

    (University of Gothenburg)

  • Eicke Latz

    (University of Bonn
    University of Massachusetts Medical School
    German Center for Neurodegenerative Diseases)

  • Benjamin Lelouvier

    (Vaiomer SAS)

  • Julio Saez-Rodriguez

    (Faculty of Medicine, and Heidelberg University Hospital
    Faculty of Medicine)

  • Willem de Vos

    (Wageningen University
    University of Helsinki)

  • Till Strowig

    (Germany and Hannover Medical School)

  • Jonel Trebicka

    (European Foundation for the Study of Chronic Liver Failure (EF-CLIF)
    Goethe University Frankfurt)

  • Christian Trautwein

    (University Hospital RWTH Aachen)

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.

Suggested Citation

  • 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 & Caroli, 2022. "Imbalanced gut microbiota fuels hepatocellular carcinoma development by shaping the hepatic inflammatory microenvironment," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31312-5
    DOI: 10.1038/s41467-022-31312-5
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    Cited by:

    1. Wenfang Gui & Mikal Jacob Hole & Antonio Molinaro & Karolina Edlund & Kristin K. Jørgensen & Huan Su & Brigitte Begher-Tibbe & Nikolaus Gaßler & Carolin V. Schneider & Uthayakumar Muthukumarasamy & An, 2023. "Colitis ameliorates cholestatic liver disease via suppression of bile acid synthesis," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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