Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells
Chi Ma, Miaojun Han, Bernd Heinrich, Qiong Fu, Qianfei Zhang, Milan Sandhu, David Agdashian, Masaki Terabe, Jay A Berzofsky, Valerie Fako, Thomas Ritz, Thomas Longerich, Casey M Theriot, John A McCulloch, Soumen Roy, Wuxing Yuan, Vishal Thovarai, Shurjo K Sen, Mathuros Ruchirawat, Firouzeh Korangy, Xin Wei Wang, Giorgio Trinchieri, Tim F Greten, Chi Ma, Miaojun Han, Bernd Heinrich, Qiong Fu, Qianfei Zhang, Milan Sandhu, David Agdashian, Masaki Terabe, Jay A Berzofsky, Valerie Fako, Thomas Ritz, Thomas Longerich, Casey M Theriot, John A McCulloch, Soumen Roy, Wuxing Yuan, Vishal Thovarai, Shurjo K Sen, Mathuros Ruchirawat, Firouzeh Korangy, Xin Wei Wang, Giorgio Trinchieri, Tim F Greten
Abstract
Primary liver tumors and liver metastasis currently represent the leading cause of cancer-related death. Commensal bacteria are important regulators of antitumor immunity, and although the liver is exposed to gut bacteria, their role in antitumor surveillance of liver tumors is poorly understood. We found that altering commensal gut bacteria in mice induced a liver-selective antitumor effect, with an increase of hepatic CXCR6+ natural killer T (NKT) cells and heightened interferon-γ production upon antigen stimulation. In vivo functional studies showed that NKT cells mediated liver-selective tumor inhibition. NKT cell accumulation was regulated by CXCL16 expression of liver sinusoidal endothelial cells, which was controlled by gut microbiome-mediated primary-to-secondary bile acid conversion. Our study suggests a link between gut bacteria-controlled bile acid metabolism and liver antitumor immunosurveillance.
Conflict of interest statement
Competing interests: C.M and T.F.G are inventors on a patent application (U.S. Patent Application no. 62/578,176) submitted by the National Cancer Institute that covers the use of bile acids to treat and/or prevent adverse liver conditions The authors declare no other competing interests.
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Source: PubMed