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Gut microbiota
Original article
Gut microbiome analysis as a tool towards targeted non-invasive biomarkers for early hepatocellular carcinoma
  1. Zhigang Ren1,2,3,
  2. Ang Li2,3,4,
  3. Jianwen Jiang1,4,5,
  4. Lin Zhou1,4,
  5. Zujiang Yu2,3,
  6. Haifeng Lu4,
  7. Haiyang Xie1,4,
  8. Xiaolong Chen2,3,
  9. Li Shao4,
  10. Ruiqing Zhang6,7,
  11. Shaoyan Xu1,
  12. Hua Zhang4,
  13. Guangying Cui2,3,
  14. Xinhua Chen1,4,
  15. Ranran Sun2,3,
  16. Hao Wen7,
  17. Jan P Lerut8,
  18. Quancheng Kan9,
  19. Lanjuan Li4,
  20. Shusen Zheng1,4,10
  1. 1 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
  2. 2 Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
  3. 3 Gene Hospital of Henan Province; Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
  4. 4 State Key Laboratory for Diagnosis and Treatment of Infectious Disease; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China
  5. 5 Health Management Center, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
  6. 6 Hepatobiliary and Hydatid Department, Digestive and Vascular Surgery Centre, Xinjiang Key Laboratory of Echinococcosis, the First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
  7. 7 State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, Xinjiang, China
  8. 8 Starzl Unit Abdominal Transplantation, University Hospitals Saint Luc, Université catholique Louvain, UCL Brussels, Brussels, Belgium
  9. 9 Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
  10. 10 Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou, China
  1. Correspondence to Professor Quancheng Kan, Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; qckan19632012{at}163.com, 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; ljli{at}zju.edu.cn and Professor Shusen Zheng, Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; shusenzheng{at}zju.edu.cn

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.

  • hepatocellular carcinoma
  • liver cirrhosis
  • gut microbiota
  • early diagnosis

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/.

https://doi.org/10.1136/gutjnl-2017-315084

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    Footnotes

    • ZR, AL, JJ, LZ and ZY contributed equally.

    • Contributors Study concept and design: SZ, LL and QK. Acquisition of data: ZR, JJ, LZ, ZY, HL, XC, RZ, SX, HZ, XC and GC. Analysis and interpretation of data: AL, LS and RS. Technical and material support: LZ, HX, ZY and HW. Drafting of the manuscript: ZR, GC and JL.

    • Funding This study was sponsored by grants from National S&T Major Project of China (2017ZX10203205 and 2018ZX10301201), Innovative Research Groups of National Natural Science Foundation of China (81721091), National Natural Science Foundation of China (81600506, 81672422, 81702757 and 81702346), Major program of National Natural Science Foundation of China (91542205) and China Postdoctoral Science Foundation (2017464 and 20182814), Open Project in State Key Laboratory for Diagnosis and Treatment of Infectious Disease (2015KF03), Natural Science Foundation of Zhejiang Province (LY15H160033), Zhejiang Province Health Department Program (2014KYB081 and 2017KY322), Youth innovation fund of First Affiliated Hospital of Zhengzhou University (YNQN2017032 and YNQN2017031), Joint research fund of First Affiliated Hospital of Zhengzhou University and Dalian Institute of Chemical Physics, Chinese Academy of Sciences (RZG and SRR).

    • Disclaimer The funding sources had no role in the design of this study nor any role during its execution, analyses, data interpretation or decision to submit results.

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval This study was approved by the Institutional Review Board of the First Affiliated Hospital, School of Medicine, Zhejiang University (2014-334), the First Affiliated Hospital of Zhengzhou University (2017-XY-002) and the First Affiliated Hospital of Xinjiang Medical University. The study was performed in accordance with the Helsinki Declaration and Rules of Good Clinical Practice. All participants signed written informed consents after the study protocol was fully explained.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement The raw Illumina read data for all samples were deposited in the European Bioinformatics Institute European Nucleotide Archive database under the accession number PRJEB8708.