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Original research
Gut commensal Parabacteroides distasonis alleviates inflammatory arthritis
  1. Haijian Sun1,2,
  2. Yunke Guo3,
  3. Haidan Wang3,
  4. Ailing Yin4,
  5. Jing Hu5,
  6. Tianjie Yuan6,
  7. Shuxin Zhou7,
  8. Weichen Xu6,
  9. Peng Wei3,
  10. Shusheng Yin8,
  11. Panru Liu1,
  12. Xi Guo1,
  13. Yizhao Tang1,
  14. Yujiao Yan8,
  15. Zichen Luo6,
  16. Majie Wang9,
  17. Qingqing Liang10,
  18. Peng Wu10,
  19. Aifeng Zhang11,
  20. Zhuxiu Zhou8,
  21. Yueyue Chen4,
  22. Yongming Li8,
  23. Jing Li7,
  24. Jinjun Shan6,
  25. Wei Zhou1
  1. 1State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
  2. 2Wuxi School of Medicine, Jiangnan University, Wuxi, China
  3. 3Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
  4. 4Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
  5. 5Department of Rheumatology, The Affiliated Jiangyin Hospital of Southeast University, Jiangyin, China
  6. 6Institute of Pediatrics, Jiangsu Key Laboratory of Pediatric Respiratory Disease, Medical Metabolomics Center, Nanjing University of Chinese Medicine, Nanjing, China
  7. 7School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
  8. 8School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
  9. 9Key Laboratory of Addiction Research of Zhejiang Province, Ningbo Kangning Hospital, Ningbo, China
  10. 10LC-Bio Technology Co., Ltd, Hangzhou, China
  11. 11Department of Pathology, Medical School of Southeast University, Nanjing, China
  1. Correspondence to Dr Wei Zhou, State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China; wzhou{at}cpu.edu.cn; Dr Jinjun Shan, Institute of Pediatrics, Jiangsu Key Laboratory of Pediatric Respiratory Disease, Medical Metabolomics Center, Nanjing University of Chinese Medicine, Nanjing, China; jshan{at}njucm.edu.cn; Dr Jing Li, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China; lj_cpu{at}126.com; Dr Yongming Li, School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China; liyongming1979{at}sina.com

Abstract

Objective Gut microbiota dysbiosis is closely linked to the pathogenesis of rheumatoid arthritis (RA). We aimed to identify potential probiotic gut microbes that can ameliorate the development of RA.

Design Microbiota profiling in patients with RA and healthy individuals was investigated via 16S rDNA bacterial gene sequencing and shotgun metagenomics. Collagen-induced arthritic mice and TNF-α transgenic mice were used to evaluate the roles of the gut commensal Parabacteroides distasonis in RA. The effects of P. distasonis-derived microbial metabolites on the differentiation of CD4+ T cells and macrophage polarisation were also investigated.

Results The relative abundance of P. distasonis in new-onset patients with RA and patients with RA with history of the disease was downregulated and this decrease was negatively correlated with Disease Activity Score-28 (DAS28). Oral treatment of arthritic mice with live P. distasonis (LPD) considerably ameliorated RA pathogenesis. LPD-derived lithocholic acid (LCA), deoxycholic acid (DCA), isolithocholic acid (isoLCA) and 3-oxolithocholic acid (3-oxoLCA) had similar and synergistic effects on the treatment of RA. In addition to directly inhibiting the differentiation of Th17 cells, 3-oxoLCA and isoLCA were identified as TGR5 agonists that promoted the M2 polarisation of macrophages. A specific synthetic inhibitor of bile salt hydrolase attenuated the antiarthritic effects of LPD by reducing the production of these four bile acids. The natural product ginsenoside Rg2 exhibited its anti-RA effects by promoting the growth of P. distasonis.

Conclusions P. distasonis and ginsenoside Rg2 might represent probiotic and prebiotic agents in the treatment of RA.

  • arthritis
  • Intestinal microbiology
  • bile acid metabolism
  • inflammation

Data availability statement

Data are available on reasonable request. The data of 16S rDNA bacteria gene sequencing have been deposited to the SRA database in NCBI (PRJNA786110 and PRJNA785810). The data of shotgun metagenomic sequencing have been deposited to the SRA database in NCBI (PRJNA896336). All data relevant to the study are included in the article or uploaded as online supplemental information.

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Data availability statement

Data are available on reasonable request. The data of 16S rDNA bacteria gene sequencing have been deposited to the SRA database in NCBI (PRJNA786110 and PRJNA785810). The data of shotgun metagenomic sequencing have been deposited to the SRA database in NCBI (PRJNA896336). All data relevant to the study are included in the article or uploaded as online supplemental information.

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Footnotes

  • HS, YG, HW and AY are joint first authors.

  • Correction notice This article has been corrected since it published Online First. The author corresponding details and ethics approval statement have been updated.

  • Contributors WZ, JS, JL and YL designed and supervised the study. WZ, HS, TY, MW, PW and QL collected and analysed the data. YG, ZZ, AY, YC and JH recruited subjects and collected samples. HW, PW, WX, SY, PL, XG, YT, YY, ZL, TY, SZ and AZ conducted animal, bacterial cultivation and mass spectrometry experiments. WZ and HS wrote the manuscript. WZ, HS, JS and YL contributed to text revision and discussion. WZ was responsible for the overall content of this study. All authors discussed the results and approved the manuscript.

  • Funding This work was financially supported by the National Natural Science Foundation of China (82274071, 82170424, 82174098 and 81803694), high-level introduction of talents and scientific research start-up funds of CPU (3150020068), the Natural Science Foundation of Jiangsu Province (BK20170179 and BK20161573), the Fundamental Research Funds for the Central Universities (Grant No. 2632020ZD07), the Major Research Plan of Natural Science Foundation of the Higher Education Institutions of Jiangsu Province (16KJA360002), Jiangsu Provincial 333 High Levels Talents Cultivation Project (BRA2016427), Jiangsu Provincial Six Talent Peaks Project (YY-022), Qing Lan Project, and the Open Projects of the Discipline of Chinese Medicine of Nanjing University of Chinese Medicine Supported by the Subject of Academic priority discipline of Jiangsu Higher Education Institutions (ZYX03KF050).

  • 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.