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  • Rheumatoid arthritis patients harbour aberrant enteric bacteriophages with autoimmunity-provoking potential: a paired sibling study

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Rheumatoid arthritis
Rheumatoid arthritis patients harbour aberrant enteric bacteriophages with autoimmunity-provoking potential: a paired sibling study
  1. Fanlei Hu1,2,3,
  2. Xin Li1,4,
  3. Kai Liu5,6,
  4. Yanpeng Li7,
  5. Yang Xie1,
  6. Chaonan Wei1,
  7. Shuyan Liu1,
  8. Jing Song1,4,
  9. Ping Wang1,
  10. Lianjie Shi8,
  11. Chun Li1,
  12. Jing Li1,
  13. Liling Xu1,
  14. Jimeng Xue1,
  15. Xi Zheng1,4,
  16. Mingxin Bai1,
  17. Xiangyu Fang1,
  18. Xu Jin1,4,
  19. Lulu Cao1,
  20. Pei Hao5,
  21. Jing He1,
  22. Jun Wang9,
  23. Chiyu Zhang5,7,
  24. Zhanguo Li1,2,4
  1. 1 Department of Rheumatology and Immunology, Peking University People’s Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
  2. 2 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
  3. 3 Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China
  4. 4 Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
  5. 5 Key Laboratory of Molecular Virology and Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, University of Chinese Academy of Sciences, shanghai, China
  6. 6 Department of Clinical Laboratory, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai, China
  7. 7 Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
  8. 8 Department of Rheumatology and Immunology, Peking University Shougang Hospital, Beijing, China
  9. 9 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Science, Beijing, China
  1. Correspondence to Professor Fanlei Hu; fanleihu{at}bjmu.edu.cn; Professor Zhanguo Li; li99{at}bjmu.edu.cn

Abstract

Objectives Viruses have been considered as important participants in the development of rheumatoid arthritis (RA). However, the profile of enteric virome and its role in RA remains elusive. This study aimed to investigate the atlas and involvement of virome in RA pathogenesis.

Methods Faecal samples from 30 pairs of RA and healthy siblings that minimise genetic interferences were collected for metagenomic sequencing. The α and β diversity of the virome and the virome–bacteriome interaction were analysed. The differential bacteriophages were identified, and their correlations with clinical and immunological features of RA were analysed. The potential involvement of these differential bacteriophages in RA pathogenesis was further investigated by auxiliary metabolic gene annotation and molecular mimicry study. The responses of CD4+ T cells and B cells to the mimotopes derived from the differential bacteriophages were systemically studied.

Results The composition of the enteric bacteriophageome was distorted in RA. The differentially presented bacteriophages correlated with the immunological features of RA, including anti-CCP autoantibody and HLA-DR shared epitope. Intriguingly, the glycerolipid and purine metabolic genes were highly active in the bacteriophages from RA. Moreover, peptides of RA-enriched phages, in particular Prevotella phage and Oscillibacter phage could provoke the autoimmune responses in CD4+ T cells and plasma cells via molecular mimicry of the disease-associated autoantigen epitopes, especially those of Bip.

Conclusions This study provides new insights into enteric bacteriophageome in RA development. In particular, the aberrant bacteriophages demonstrated autoimmunity-provoking potential that would promote the occurrence of the disease.

  • Rheumatoid Arthritis
  • Autoimmunity
  • Therapeutics

Data availability statement

Data are available in a public, open access repository. The virome and 16S rDNA sequencing data have been deposited in the NCBI Sequence Read Archive (SRA) under the accession number PRJNA686769 and PRJNA686809, respectively. All the used scripts and intermediate data files have also been uploaded to GitHub (https://github.com/kyle-lk/RA_virome.git).

https://doi.org/10.1136/ard-2024-225564

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    Data availability statement

    Data are available in a public, open access repository. The virome and 16S rDNA sequencing data have been deposited in the NCBI Sequence Read Archive (SRA) under the accession number PRJNA686769 and PRJNA686809, respectively. All the used scripts and intermediate data files have also been uploaded to GitHub (https://github.com/kyle-lk/RA_virome.git).

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    Footnotes

    • Handling editor Josef S Smolen

    • FH, XL and KL contributed equally.

    • Contributors Performed the experiments: FH, XL, YL and YX; Analysed the data: FH, XL, KL and YL; Contributed reagents/materials/analysis tools: CW, SL, JS, PW, LS, CL, JL, LX, JX, XZ, MB, XF, XJ, LC, PH and JH; Wrote the manuscript: FH and XL; Reviewed and edited the manuscript: ZL, FH, CZ and JW. Conceived and designed the study: ZL and FH. Guarantor: ZL.

    • Funding This work was supported by grants from the National Natural Science Foundation of China (82371807, 82171773, 81971523, and 81671604 to Dr F Hu, 92374202, 32141004, and U1903210 to Dr Z Li), the National Key R&D Program of China (2022YFC3602000), and the Beijing Nova Program (Z181100006218044 and Z211100002121163 to Dr F Hu), as well as by the Guangdong Basic and Applied Basic Research Foundation Funds (2020B1515130005 to Dr Z Li), the Fundamental Research Funds for the Central Universities: Peking University Clinical Medicine Plus X-Young Scholars Project (PKU2023LCXQ003 to Dr F Hu), and Peking University People’s Hospital Research and Development Funds (RZ2022-01 to Dr F Hu).

    • Disclaimer The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript.

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • 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.