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Gut microbiota
Original article
Gut microbiome analysis as a tool towards targeted non-invasive biomarkers for early hepatocellular carcinoma
Zhigang Ren1,2,3, Ang Li2,3,4, Jianwen Jiang1,4,5, Lin Zhou1,4, Zujiang Yu2,3, Haifeng Lu4, Haiyang Xie1,4, Xiaolong Chen2,3, Li Shao4, Ruiqing Zhang6,7, Shaoyan Xu1, Hua Zhang4, Guangying Cui2,3, Xinhua Chen1,4, Ranran Sun2,3, Hao Wen7, Jan P Lerut8, Quancheng Kan9, Lanjuan Li4, Shusen Zheng1,4,10
Author affiliations
Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University; Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China
Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
Gene Hospital of Henan Province; Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
State Key Laboratory for Diagnosis and Treatment of Infectious Disease; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China
Health Management Center, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Hepatobiliary and Hydatid Department, Digestive and Vascular Surgery Centre, Xinjiang Key Laboratory of Echinococcosis, the First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, Xinjiang, China
Starzl Unit Abdominal Transplantation, University Hospitals Saint Luc, Université catholique Louvain, UCL Brussels, Brussels, Belgium
Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou, China
Correspondence to Professor Quancheng Kan, Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; [email protected], Professor Lanjuan Li, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; [email protected] and Professor Shusen Zheng, Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; [email protected]
Abstract
Objective To characterise gut microbiome in patients with hepatocellular carcinoma (HCC) and evaluate the potential of microbiome as non-invasive biomarkers for HCC.
Design We collected 486 faecal samples from East China, Central China and Northwest China prospectively and finally 419 samples completed Miseq sequencing. We characterised gut microbiome, identified microbial markers and constructed HCC classifier in 75 early HCC, 40 cirrhosis and 75 healthy controls. We validated the results in 56 controls, 30 early HCC and 45 advanced HCC. We further verified diagnosis potential in 18 HCC from Xinjiang and 80 HCC from Zhengzhou.
Results Faecal microbial diversity was increased from cirrhosis to early HCC with cirrhosis. Phylum Actinobacteria was increased in early HCC versus cirrhosis. Correspondingly, 13 genera including Gemmiger and Parabacteroides were enriched in early HCC versus cirrhosis. Butyrate-producing genera were decreased, while genera producing-lipopolysaccharide were increased in early HCC versus controls. The optimal 30 microbial markers were identified through a fivefold cross-validation on a random forest model and achieved an area under the curve of 80.64% between 75 early HCC and 105 non-HCC samples. Notably, gut microbial markers validated strong diagnosis potential for early HCC and even advanced HCC. Importantly, microbial markers successfully achieved a cross-region validation of HCC from Northwest China and Central China.
Conclusions This study is the first to characterise gut microbiome in patients with HCC and to report the successful diagnosis model establishment and cross-region validation of microbial markers for HCC. Gut microbiota-targeted biomarkers represent potential non-invasive tools for early diagnosis of HCC.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
http://dx.doi.org/10.1136/gutjnl-2017-315084
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Significance of this study
What is already known on this subject?
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide due to the poor prognosis, high incidence and postsurgical recurrence.
The gut microbiota promotes HCC development by the microbiota-liver axis in HCC animal models, but microbial characteristics in patients with HCC have not been reported.
The concept of the gut microbiome serving as a tool towards for achieving targeted non-invasive biomarkers for specific diseases or cancer, including type 2 diabetes, liver cirrhosis and colorectal cancer, has been established by compelling studies, but it is unclear whether gut microbial markers could discriminate HCC.
What are the new findings?
Faecal microbial diversity was decreased from healthy controls to cirrhosis, but it was increased from cirrhosis to early HCC with cirrhosis.
Butyrate-producing bacterial genera were decreased, while genera producing-lipopolysaccharide were increased in early HCC versus healthy controls.
The optimal 30 microbial markers were identified through a fivefold cross-validation on a random forest model and achieved an area under the curve of 80.64% between 75 early HCC and 105 non-HCC samples.
Gut microbial markers validated strong diagnosis potential for early HCC and even advanced HCC. Importantly, microbial markers successfully achieved a cross-region validation of HCC from Northwest China and Central China.
Significance of this study
How might it impact on clinical practice in the foreseeable future?
This is the first report to illustrate gut microbial characteristics in patients with early HCC through large-cohort Miseq sequencing.
Gut microbial alterations may contribute to the development of HCC, which implies that the changed gut microbiota may represent a potential target to prevent HCC development by the gut-microbiota-liver axis.
This study is the first to report the successful diagnosis model establishment and cross-region validation of microbial markers for HCC, notably including data from three different regions of China. Gut microbiota-targeted biomarkers represent potential non-invasive tools for early diagnosis of HCC. |
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发表于 2018-7-26 15:42