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Hepatology
Original research
PBMC transcriptomics identifies immune-metabolism disorder during the development of HBV-ACLF
  1. Jiang Li1,
  2. Xi Liang2,3,
  3. Jing Jiang1,2,
  4. Lingling Yang1,
  5. Jiaojiao Xin1,2,
  6. Dongyan Shi1,2,
  7. Yingyan Lu4,
  8. Jun Li5,
  9. Keke Ren1,
  10. Hozeifa Mohamed Hassan1,
  11. Jianing Zhang6,
  12. Pengcheng Chen3,
  13. Heng Yao1,
  14. Jiaqi Li1,
  15. Tianzhou Wu2,
  16. Linfeng Jin1,
  17. Ping Ye1,
  18. Tan Li1,
  19. Huafen Zhang1,
  20. Suwan Sun1,
  21. Beibei Guo1,
  22. Xingping Zhou1,
  23. Qun Cai1,
  24. Jiaxian Chen1,
  25. Xiaowei Xu1,
  26. Jianrong Huang1,
  27. Shaorui Hao1,
  28. Jinqiu He7,
  29. Shaojie Xin8,
  30. Di Wang9,
  31. Jonel Trebicka10,11,
  32. Xin Chen12,13,
  33. Jun Li1,2
  34. Chinese Group on the Study of Severe Hepatitis B (COSSH)
  1. 1 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
  2. 2 Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
  3. 3 Institute of Pharmaceutical Biotechnology, Zhejiang University School of Medicine, Hangzhou, China
  4. 4 Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, China
  5. 5 Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
  6. 6 The State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, China
  7. 7 The Liver Disease Department, The Ninth Hospital of Nanchang, Nanchang, China
  8. 8 Department of Liver and Infectious Diseases, The Fifth Medical Center of PLA General Hospital, Beijing, China
  9. 9 Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China
  10. 10 Translational Hepatology, Department of Internal Medicine I, University Clinic Frankfurt, Frankfurt, Germany
  11. 11 EF Clif, European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
  12. 12 Institute of Pharmaceutical Biotechnology and the First Affiliated Hospital Department of Radiation Oncology, Zhejiang University School of Medicine, Hangzhou, 310058, China
  13. 13 Joint Institute for Genetics and Genome Medicine between Zhejiang University and University of Toronto, Zhejiang University, Hangzhou, China
  1. Correspondence to Professor Jun Li, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine First Affiliated Hospital, Hangzhou, Zhejiang, China; lijun2009{at}zju.edu.cn; Professor Xin Chen; xinchen{at}zju.edu.cn; Professor Jonel Trebicka; jonel.trebicka{at}efclif.com; Professor Di Wang; diwang{at}zju.edu.cn

Abstract

Objective Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) pathophysiology remains unclear. This study aims to characterise the molecular basis of HBV-ACLF using transcriptomics.

Methods Four hundred subjects with HBV-ACLF, acute-on-chronic hepatic dysfunction (ACHD), liver cirrhosis (LC) or chronic hepatitis B (CHB) and normal controls (NC) from a prospective multicentre cohort were studied, and 65 subjects (ACLF, 20; ACHD, 10; LC, 10; CHB, 10; NC, 15) among them underwent mRNA sequencing using peripheral blood mononuclear cells (PBMCs).

Results The functional synergy analysis focusing on seven bioprocesses related to the PBMC response and the top 500 differentially expressed genes (DEGs) showed that viral processes were associated with all disease stages. Immune dysregulation, as the most prominent change and disorder triggered by HBV exacerbation, drove CHB or LC to ACHD and ACLF. Metabolic disruption was significant in ACHD and severe in ACLF. The analysis of 62 overlapping DEGs further linked the HBV-based immune-metabolism disorder to ACLF progression. The signatures of interferon-related, neutrophil-related and monocyte-related pathways related to the innate immune response were significantly upregulated. Signatures linked to the adaptive immune response were downregulated. Disruptions of lipid and fatty acid metabolism were observed during ACLF development. External validation of four DEGs underlying the aforementioned molecular mechanism in patients and experimental rats confirmed their specificity and potential as biomarkers for HBV-ACLF pathogenesis.

Conclusions This study highlights immune-metabolism disorder triggered by HBV exacerbation as a potential mechanism of HBV-ACLF and may indicate a novel diagnostic and treatment target to reduce HBV-ACLF-related mortality.

  • liver failure
  • hepatitis B
  • cirrhosis

Data availability statement

Data, that is raw reads from RNA-seq experiments in fastq files, are available in a public, open access repository without restrictions on the use or distribution of the data. The Sequence Read Archive database project accession number for accessing the data produced for this study is PRJNA548207 (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA548207/).

http://creativecommons.org/licenses/by-nc/4.0/

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-2020-323395

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    Data availability statement

    Data, that is raw reads from RNA-seq experiments in fastq files, are available in a public, open access repository without restrictions on the use or distribution of the data. The Sequence Read Archive database project accession number for accessing the data produced for this study is PRJNA548207 (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA548207/).

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    Footnotes

    • Twitter @lijun2009

    • Correction notice This article has been corrected since it published Online First. The provenance and peer review statement has been included.

    • Contributors JL (first author), XL, JJ and LY contributed equally. The study was designed by JL (last author) and XC. The manuscript was written by JL (last author), XC, JT, JL (first author), XL and DW. The experiments and data analysis were performed by JL (first author), XL, JJ, LY, JX, DS, YL, JL (8thauthor), KR, HH, JZ, PC, HY, JL (14th author), TW, LJ, PY, TL, HZ, SS, BG, XZ, QC, JC, XX, JH (26th author), SH, JH (28th author), SX, DW, JT, XC and JL (last author). JL (Last author) supported and supervised the project. All authors were involved in the critical revision of the manuscript.

    • Funding This study was supported by the National Natural Science Foundation of China (81830073), the National S&T Major Project of China (2017ZX10203201), the Zhejiang Provincial and State’s Key Project of Research and Development Plan of China (2016YFC1101303/4 and 2017C01026) and the National and Zhejiang Provincial special support programme for high-level personnel recruitment (Ten-thousand Talents Programme).

    • Competing interests None declared.

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

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.