Gut Pathobionts Translocate into the Liver and Reshape Intrahepatic Microbiome to Facilitate Hepatocellular Carcinoma
7 affiliations
- 1Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China.
- 2Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
- 3Department of Oncology, Cancer Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
- 4Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
- 5Advanced Medical Technology Centre, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
- 6Clinical Trials Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
- 7Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Abstract
The role of intrahepatic microbiome in hepatocellular carcinoma (HCC) remains elusive. In this study, we profiled matched gut and intrahepatic microbiomes from patients with HCC and healthy subjects. Compared with healthy subjects, we observed increased gut–liver microbiome similarity and a gut pathobiont–centered network in HCC, implying microbial transfer via the gut–liver axis. Consistently, HCC stool transplantation to germ-free mice impaired gut barrier function and increased bacterial load in the liver. Multisite 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 the liver. B. fragilis exacerbated liver damage and promoted HCC development in mice. Mechanistically, B. fragilis surface protein enolase interacts with and activates vimentin on hepatocytes, triggering oncogenic cascades. Our findings provide insight into how gut pathobionts translocate to the liver to promote hepatocarcinogenesis.
Significance:: Parallel characterization of stool and intrahepatic microbiomes from patients with HCC and healthy subjects revealed gut–liver microbial transfer. The gut pathobiont B. fragilis disrupts gut barrier and translocates as live bacteria to the liver. Its surface protein enolase binds hepatocyte vimentin to activate proinflammatory and oncogenic signaling, thereby promoting liver tumorigenesis.
See related commentary by Chojnacka and Grivennikov, p. 2214
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BibTeX
@article{liu2026pathobionts,
title = {{Gut Pathobionts Translocate into the Liver and Reshape Intrahepatic Microbiome to Facilitate Hepatocellular Carcinoma}},
author = {Weixin Liu and Xueliang Wang and Ying Zhang and Jinkai Liu and Meiyi Li and Qianying Zhou and Lina Wang and Shimao Liu and Weikang Chen and Eagle S.H. Chu and Harry Cheuk-Hay Lau and Qian Song and Xingyu Zhou and Hongyan Gou and Jennifer Xiang Zhang and Guo-Bao Tian and Liangjing Wang and Xiaoxing Li and Sui Peng and Chi Chun Wong and Ming Kuang and Lixia Xu and Jun Yu},
journal = {Cancer Discovery},
year = {2026},
month = jun,
doi = {10.1158/2159-8290.cd-25-1355},
url = {https://doi.org/10.1158/2159-8290.cd-25-1355},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Gut Pathobionts Translocate into the Liver and Reshape Intrahepatic Microbiome to Facilitate Hepatocellular Carcinoma
AU - Weixin Liu
AU - Xueliang Wang
AU - Ying Zhang
AU - Jinkai Liu
AU - Meiyi Li
AU - Qianying Zhou
AU - Lina Wang
AU - Shimao Liu
AU - Weikang Chen
AU - Eagle S.H. Chu
AU - Harry Cheuk-Hay Lau
AU - Qian Song
AU - Xingyu Zhou
AU - Hongyan Gou
AU - Jennifer Xiang Zhang
AU - Guo-Bao Tian
AU - Liangjing Wang
AU - Xiaoxing Li
AU - Sui Peng
AU - Chi Chun Wong
AU - Ming Kuang
AU - Lixia Xu
AU - Jun Yu
PY - 2026
DA - 2026/06/04
JO - Cancer Discovery
DO - 10.1158/2159-8290.cd-25-1355
UR - https://doi.org/10.1158/2159-8290.cd-25-1355
AB - The role of intrahepatic microbiome in hepatocellular carcinoma (HCC) remains elusive. In this study, we profiled matched gut and intrahepatic microbiomes from patients with HCC and healthy subjects. Compared with healthy subjects, we observed increased gut–liver microbiome similarity and a gut pathobiont–centered network in HCC, implying microbial transfer via the gut–liver axis. Consistently, HCC stool transplantation to germ-free mice impaired gut barrier function and increased bacterial load in the liver. Multisite 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 the liver. B. fragilis exacerbated liver damage and promoted HCC development in mice. Mechanistically, B. fragilis surface protein enolase interacts with and activates vimentin on hepatocytes, triggering oncogenic cascades. Our findings provide insight into how gut pathobionts translocate to the liver to promote hepatocarcinogenesis. Significance:: Parallel characterization of stool and intrahepatic microbiomes from patients with HCC and healthy subjects revealed gut–liver microbial transfer. The gut pathobiont B. fragilis disrupts gut barrier and translocates as live bacteria to the liver. Its surface protein enolase binds hepatocyte vimentin to activate proinflammatory and oncogenic signaling, thereby promoting liver tumorigenesis. See related commentary by Chojnacka and Grivennikov, p. 2214
SN - 2159-8274
SN - 2159-8290
ER -