Catenibacterium mitsuokai promotes hepatocellular carcinogenesis by binding to hepatocytes and generating quinolinic acid
Ying Zhang, Weixin Liu, Chi Chun Wong, Qian Song, Xinyue Zhang, Qianying Zhou, Xuxin Ren, Xiaoxue Ren, Ruiyan Xuan, Yutong Zhao, Linfu Xu, Xiaoxing Li, Lixia Xu, Xiang Zhang, Ming Kuang, Jun Yu
Abstract
The role of gut microbes in the pathogenesis of hepatocellular carcinoma (HCC) remains unclear. Here, we identified that Catenibacterium is enriched in both the feces and tumors of patients with HCC. C. mitsuokai accelerated HCC carcinogenesis in both conventional and germ-free mice. Furthermore, C. mitsuokai disrupted the gut barrier and translocated to the liver as live bacteria. Critically, the C. mitsuokai surface protein Gtr1/RagA interacts with the γ-catenin receptor on HCC cells, facilitating its attachment and colonization in the mouse liver. We further revealed that the pro-tumorigenic effect of C. mitsuokai depends on its secreted metabolite, quinolinic acid. Mechanistically, quinolinic acid binds to and activates the tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2 (TIE2) on HCC cells. Phosphorylated TIE2 subsequently activates the downstream oncogenic phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway, thereby promoting HCC progression. In summary, C. mitsuokai disrupts the gut barrier, colonizes HCC cells via Gtr1/RagA-γ-catenin, and secretes quinolinic acid, which binds to TIE2 and drives the PI3K/AKT pathway to promote HCC development. • C. mitsuokai is concomitantly enriched in both the feces and tumors of HCC patients • C. mitsuokai accelerates HCC carcinogenesis in conventional and germ-free mice • Live C. mitsuokai translocates to the liver and attaches to HCC by Gtr1/RagA • C. mitsuokai -secreted quinolinic acid binds to TIE2 on HCC and activates the PI3K-AKT Zhang et al. reveal that the gut bacterium Catenibacterium mitsuokai promotes hepatocellular carcinoma by disrupting the gut barrier, colonizing HCC cells via its surface protein Gtr1/RagA and receptor γ-catenin, and secreting quinolinic acid, which binds to TIE2 and activates the oncogenic PI3K/AKT pathway in HCC cells.