Gut microbiome–mediated bile acid metabolism regulates liver cancer via NKT cells

TLDR

Primary liver tumors and metastases are the leading cause of cancer death, yet the role of gut microbiota in liver antitumor immunity remains poorly understood. The study investigates whether gut bacteria‑mediated bile acid metabolism regulates liver antitumor surveillance. Gut‑derived conversion of primary to secondary bile acids controls CXCL16 expression in liver sinusoidal endothelial cells, which in turn drives accumulation of CXCR6+ NKT cells. Modifying the gut microbiome increased hepatic CXCR6+ NKT cells and interferon‑γ production, and NKT cells were shown to mediate liver‑selective tumor inhibition.

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.