Gut flora disequilibrium promotes the initiation of liver cancer by modulating tryptophan metabolism and up-regulating SREBP2

作者：Wen Chen, Liang Wen, Yingying Bao, Zengwei Tang, Jianhui Zhao, Xiaozhen Zhang, Tao Wei, Jian Zhang, Tao Ma, Qi Zhang, Xiao Zhi, Jin Li, Cheng Zhang, Lei Ni, Muchun Li, Tingbo Liang · 发表于：Proceedings of the National Academy of Sciences · 年份：2022 · DOI：10.1073/pnas.2203894119 · 被引用次数：97 · 研究领域：Gut microbiota and health、Diet and metabolism studies、Drug Transport and Resistance Mechanisms

The gut microbiota and liver cancer have a complex interaction. However, the role of gut microbiome in liver tumor initiation remains unknown. Herein, liver cancer was induced using hydrodynamic transfection of oncogenes to explore liver tumorigenesis in mice. Gut microbiota depletion promoted liver tumorigenesis but not progression. Elevated sterol regulatory element-binding protein 2 (SREBP2) was observed in mice with gut flora disequilibrium. Pharmacological inhibition of SREBP2 or Srebf2 RNA interference attenuated mouse liver cancer initiation under gut flora disequilibrium. Furthermore, gut microbiota depletion impaired gut tryptophan metabolism to activate aryl hydrocarbon receptor (AhR). AhR agonist Ficz inhibited SREBP2 posttranslationally and reversed the tumorigenesis in mice. And, AhR knockout mice recapitulated the accelerated liver tumorigenesis. Supplementation with Lactobacillus reuteri , which produces tryptophan metabolites, inhibited SREBP2 expression and tumorigenesis in mice with gut flora disequilibrium. Thus, gut flora disequilibrium promotes liver cancer initiation by modulating tryptophan metabolism and up-regulating SREBP2.