IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-31312-5.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-31312-5
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-022-31312-5?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Tae-Won Kang & Tetyana Yevsa & Norman Woller & Lisa Hoenicke & Torsten Wuestefeld & Daniel Dauch & Anja Hohmeyer & Marcus Gereke & Ramona Rudalska & Anna Potapova & Marcus Iken & Mihael Vucur & Siegfr, 2011. "Senescence surveillance of pre-malignant hepatocytes limits liver cancer development," Nature, Nature, vol. 479(7374), pages 547-551, November.
    2. Cyrielle Caussy & Anupriya Tripathi & Greg Humphrey & Shirin Bassirian & Seema Singh & Claire Faulkner & Ricki Bettencourt & Emily Rizo & Lisa Richards & Zhenjiang Z. Xu & Michael R. Downes & Ronald M, 2019. "A gut microbiome signature for cirrhosis due to nonalcoholic fatty liver disease," Nature Communications, Nature, vol. 10(1), pages 1-9, December.
    3. Peter J. Turnbaugh & Micah Hamady & Tanya Yatsunenko & Brandi L. Cantarel & Alexis Duncan & Ruth E. Ley & Mitchell L. Sogin & William J. Jones & Bruce A. Roe & Jason P. Affourtit & Michael Egholm & Be, 2009. "A core gut microbiome in obese and lean twins," Nature, Nature, vol. 457(7228), pages 480-484, January.
    4. Jacob T. Nearing & Gavin M. Douglas & Molly G. Hayes & Jocelyn MacDonald & Dhwani K. Desai & Nicole Allward & Casey M. A. Jones & Robyn J. Wright & Akhilesh S. Dhanani & André M. Comeau & Morgan G. I., 2022. "Author Correction: Microbiome differential abundance methods produce different results across 38 datasets," Nature Communications, Nature, vol. 13(1), pages 1-1, December.
    5. Andrew C. Scott & Friederike Dündar & Paul Zumbo & Smita S. Chandran & Christopher A. Klebanoff & Mojdeh Shakiba & Prerak Trivedi & Laura Menocal & Heather Appleby & Steven Camara & Dmitriy Zamarin & , 2019. "TOX is a critical regulator of tumour-specific T cell differentiation," Nature, Nature, vol. 571(7764), pages 270-274, July.
    6. Jason Behary & Nadia Amorim & Xiao-Tao Jiang & Anita Raposo & Lan Gong & Emily McGovern & Ragy Ibrahim & Francis Chu & Carlie Stephens & Hazem Jebeili & Vincenzo Fragomeli & Yen Chin Koay & Miriam Jac, 2021. "Gut microbiota impact on the peripheral immune response in non-alcoholic fatty liver disease related hepatocellular carcinoma," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    7. Michael Schubert & Bertram Klinger & Martina Klünemann & Anja Sieber & Florian Uhlitz & Sascha Sauer & Mathew J. Garnett & Nils Blüthgen & Julio Saez-Rodriguez, 2018. "Perturbation-response genes reveal signaling footprints in cancer gene expression," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    8. Jacob T. Nearing & Gavin M. Douglas & Molly G. Hayes & Jocelyn MacDonald & Dhwani K. Desai & Nicole Allward & Casey M. A. Jones & Robyn J. Wright & Akhilesh S. Dhanani & André M. Comeau & Morgan G. I., 2022. "Microbiome differential abundance methods produce different results across 38 datasets," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    9. Christoph A. Thaiss & Niv Zmora & Maayan Levy & Eran Elinav, 2016. "The microbiome and innate immunity," Nature, Nature, vol. 535(7610), pages 65-74, July.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    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.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Braden T Tierney & Yingxuan Tan & Zhen Yang & Bing Shui & Michaela J Walker & Benjamin M Kent & Aleksandar D Kostic & Chirag J Patel, 2022. "Systematically assessing microbiome–disease associations identifies drivers of inconsistency in metagenomic research," PLOS Biology, Public Library of Science, vol. 20(3), pages 1-18, March.
    2. Karen D. Corbin & Elvis A. Carnero & Blake Dirks & Daria Igudesman & Fanchao Yi & Andrew Marcus & Taylor L. Davis & Richard E. Pratley & Bruce E. Rittmann & Rosa Krajmalnik-Brown & Steven R. Smith, 2023. "Host-diet-gut microbiome interactions influence human energy balance: a randomized clinical trial," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Zachary D. Wallen & Ayse Demirkan & Guy Twa & Gwendolyn Cohen & Marissa N. Dean & David G. Standaert & Timothy R. Sampson & Haydeh Payami, 2022. "Metagenomics of Parkinson’s disease implicates the gut microbiome in multiple disease mechanisms," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    4. Maria Rita Perrone & Salvatore Romano & Giuseppe De Maria & Paolo Tundo & Anna Rita Bruno & Luigi Tagliaferro & Michele Maffia & Mattia Fragola, 2022. "Compositional Data Analysis of 16S rRNA Gene Sequencing Results from Hospital Airborne Microbiome Samples," IJERPH, MDPI, vol. 19(16), pages 1-21, August.
    5. Alexandria C. Wells & Kaito A. Hioki & Constance C. Angelou & Adam C. Lynch & Xueting Liang & Daniel J. Ryan & Iris Thesmar & Saule Zhanybekova & Saulius Zuklys & Jacob Ullom & Agnes Cheong & Jesse Ma, 2023. "Let-7 enhances murine anti-tumor CD8 T cell responses by promoting memory and antagonizing terminal differentiation," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    6. Patrick D Schloss, 2009. "A High-Throughput DNA Sequence Aligner for Microbial Ecology Studies," PLOS ONE, Public Library of Science, vol. 4(12), pages 1-9, December.
    7. John Molloy & Katrina Allen & Fiona Collier & Mimi L. K. Tang & Alister C. Ward & Peter Vuillermin, 2013. "The Potential Link between Gut Microbiota and IgE-Mediated Food Allergy in Early Life," IJERPH, MDPI, vol. 10(12), pages 1-22, December.
    8. Bharati Patel & Kadamb Patel & Shabbir Moochhala, 2020. "Diet-Derived Post-Biotic Metabolites to Promote Microbiota Function and Human Health," Biomedical Journal of Scientific & Technical Research, Biomedical Research Network+, LLC, vol. 28(2), pages 21520-21524, June.
    9. Ahmed A Metwally & Philip S Yu & Derek Reiman & Yang Dai & Patricia W Finn & David L Perkins, 2019. "Utilizing longitudinal microbiome taxonomic profiles to predict food allergy via Long Short-Term Memory networks," PLOS Computational Biology, Public Library of Science, vol. 15(2), pages 1-16, February.
    10. Hideki Ogura & Jin Gohda & Xiuyuan Lu & Mizuki Yamamoto & Yoshio Takesue & Aoi Son & Sadayuki Doi & Kazuyuki Matsushita & Fumitaka Isobe & Yoshihiro Fukuda & Tai-Ping Huang & Takamasa Ueno & Naomi Mam, 2022. "Dysfunctional Sars-CoV-2-M protein-specific cytotoxic T lymphocytes in patients recovering from severe COVID-19," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    11. Feng Xie & Xiaoxue Zhou & Peng Su & Heyu Li & Yifei Tu & Jinjin Du & Chen Pan & Xiang Wei & Min Zheng & Ke Jin & Liyan Miao & Chao Wang & Xuli Meng & Hans Dam & Peter Dijke & Long Zhang & Fangfang Zho, 2022. "Breast cancer cell-derived extracellular vesicles promote CD8+ T cell exhaustion via TGF-β type II receptor signaling," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    12. Pirjo Wacklin & Harri Mäkivuokko & Noora Alakulppi & Janne Nikkilä & Heli Tenkanen & Jarkko Räbinä & Jukka Partanen & Kari Aranko & Jaana Mättö, 2011. "Secretor Genotype (FUT2 gene) Is Strongly Associated with the Composition of Bifidobacteria in the Human Intestine," PLOS ONE, Public Library of Science, vol. 6(5), pages 1-10, May.
    13. Yunxi Liu & R. A. Leo Elworth & Michael D. Jochum & Kjersti M. Aagaard & Todd J. Treangen, 2022. "De novo identification of microbial contaminants in low microbial biomass microbiomes with Squeegee," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    14. Vanessa Rousseau & Elias Einig & Chao Jin & Julia Horn & Mathias Riebold & Tanja Poth & Mohamed-Ali Jarboui & Michael Flentje & Nikita Popov, 2023. "Trim33 masks a non-transcriptional function of E2f4 in replication fork progression," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    15. C. E. Dubé & M. Ziegler & A. Mercière & E. Boissin & S. Planes & C. A. -F. Bourmaud & C. R. Voolstra, 2021. "Naturally occurring fire coral clones demonstrate a genetic and environmental basis of microbiome composition," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    16. Adrian B. Levine & Liana Nobre & Anirban Das & Scott Milos & Vanessa Bianchi & Monique Johnson & Nicholas R. Fernandez & Lucie Stengs & Scott Ryall & Michelle Ku & Mansuba Rana & Benjamin Laxer & Java, 2024. "Immuno-oncologic profiling of pediatric brain tumors reveals major clinical significance of the tumor immune microenvironment," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    17. Mariana F. Fernández & Iris Reina-Pérez & Juan Manuel Astorga & Andrea Rodríguez-Carrillo & Julio Plaza-Díaz & Luis Fontana, 2018. "Breast Cancer and Its Relationship with the Microbiota," IJERPH, MDPI, vol. 15(8), pages 1-20, August.
    18. Moujtaba Y. Kasmani & Paytsar Topchyan & Ashley K. Brown & Ryan J. Brown & Xiaopeng Wu & Yao Chen & Achia Khatun & Donia Alson & Yue Wu & Robert Burns & Chien-Wei Lin & Matthew R. Kudek & Jie Sun & We, 2023. "A spatial sequencing atlas of age-induced changes in the lung during influenza infection," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    19. Erick Armingol & Hratch M. Baghdassarian & Cameron Martino & Araceli Perez-Lopez & Caitlin Aamodt & Rob Knight & Nathan E. Lewis, 2022. "Context-aware deconvolution of cell–cell communication with Tensor-cell2cell," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    20. Fabian Peisker & Maurice Halder & James Nagai & Susanne Ziegler & Nadine Kaesler & Konrad Hoeft & Ronghui Li & Eric M. J. Bindels & Christoph Kuppe & Julia Moellmann & Michael Lehrke & Christian Stopp, 2022. "Mapping the cardiac vascular niche in heart failure," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31312-5. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.