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

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Schneider , K M , Mohs , A , Gui , W , Galvez , E J C , Candels , L S , Hoenicke , L , Muthukumarasamy , U , Holland , C H , Elfers , C , Kilic , K , Schneider , C V , Schierwagen , R , Strnad , P , Wirtz , T H , Marschall , H-U , Latz , E , Lelouvier , B , Saez-Rodriguez , J , de Vos , W , Strowig , T , Trebicka , J & Trautwein , C 2022 , ' Imbalanced gut microbiota fuels hepatocellular carcinoma development by shaping the hepatic inflammatory microenvironment ' , Nature Communications , vol. 13 , no. 1 , 3964 . https://doi.org/10.1038/s41467-022-31312-5

Title: Imbalanced gut microbiota fuels hepatocellular carcinoma development by shaping the hepatic inflammatory microenvironment
Author: Schneider, Kai Markus; Mohs, Antje; Gui, Wenfang; Galvez, Eric J. C.; Candels, Lena Susanna; Hoenicke, Lisa; Muthukumarasamy, Uthayakumar; Holland, Christian H.; Elfers, Carsten; Kilic, Konrad; Schneider, Carolin Victoria; Schierwagen, Robert; Strnad, Pavel; Wirtz, Theresa H.; Marschall, Hanns-Ulrich; Latz, Eicke; Lelouvier, Benjamin; Saez-Rodriguez, Julio; de Vos, Willem; Strowig, Till; Trebicka, Jonel; Trautwein, Christian
Contributor organization: Willem Meindert Vos de / Principal Investigator
de Vos & Salonen group
Research Programs Unit
University of Helsinki
HUMI - Human Microbiome Research
Date: 2022-07-08
Language: eng
Number of pages: 19
Belongs to series: Nature Communications
ISSN: 2041-1723
DOI: https://doi.org/10.1038/s41467-022-31312-5
URI: http://hdl.handle.net/10138/346582
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. Steatohepatitis is a chronic hepatic inflammation associated with increased risk of hepatocellular carcinoma progression. Here the authors show that intestinal dysbiosis in mice lacking the inflammasome sensor molecule NLRP6 aggravates steatohepatitis and accelerates liver cancer progression, a process that can be delayed by antibiotic treatment.
Subject: NF-KAPPA-B
T-CELLS
SUPPRESSOR-CELLS
AKKERMANSIA-MUCINIPHILA
INTESTINAL MICROBIOTA
LIVER FIBROSIS
CROSS-TALK
CANCER
STEATOHEPATITIS
DYSBIOSIS
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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