Gut pathobionts translocate into liver and reshape intrahepatic microbiome to facilitate hepatocellular carcinoma

The role of intrahepatic microbiome in hepatocellular carcinoma (HCC) remains elusive. Here, we profiled matched gut and intrahepatic microbiomes from HCC patients and healthy subjects. Compared to healthy subjects, we observed increased gut-liver microbiome similarity and a gut pathobionts-centred network in HCC, implying microbial transfer via gut-liver axis. Consistently, HCC stool transplantation to germ-free mice impaired gut barrier function and increased bacterial load in liver. Multi-site analysis of intrahepatic microbiome and host transcriptome revealed that gut pathobionts in tumor regions positively correlate with host cytokine expression and oncogenic pathways. Administration of HCC-enriched Bacteroides fragilis disrupted gut barrier in mice and led to live bacteria translocation to liver. Bacteroides fragilis exacerbated liver damage and promoted HCC development in mice. Mechanistically, Bacteroides fragilis surface protein Enolase interacts with and activates Vimentin on hepatocytes, triggering oncogenic cascades. Our findings provide insight into how gut pathobionts translocate to liver to promote hepatocarcinogenesis.