Abstract

We carried out metagenomic shotgun sequencing and a metagenome-wide association study (MGWAS) of fecal, dental and salivary samples from a cohort of individuals with rheumatoid arthritis (RA) and healthy controls. Concordance was observed between the gut and oral microbiomes, suggesting overlap in the abundance and function of species at different body sites. Dysbiosis was detected in the gut and oral microbiomes of RA patients, but it was partially resolved after RA treatment. Alterations in the gut, dental or saliva microbiome distinguished individuals with RA from healthy controls, were correlated with clinical measures and could be used to stratify individuals on the basis of their response to therapy. In particular, Haemophilus spp. were depleted in individuals with RA at all three sites and negatively correlated with levels of serum autoantibodies, whereas Lactobacillus salivarius was over-represented in individuals with RA at all three sites and was present in increased amounts in cases of very active RA. Functionally, the redox environment, transport and metabolism of iron, sulfur, zinc and arginine were altered in the microbiota of individuals with RA. Molecular mimicry of human antigens related to RA was also detectable. Our results establish specific alterations in the gut and oral microbiomes in individuals with RA and suggest potential ways of using microbiome composition for prognosis and diagnosis.

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Acknowledgements

This research was supported by the Natural Science Foundation of China (grants 30890032 and 30725008 to Jun Wang and 81325019 to X.Z.), the Shenzhen Municipal Government of China (grant BGI20100001 to Jun Wang and grants JSGG20140702161403250 and DRC-SZ[2015]162 to Q.F.), the Danish Strategic Research Council (grant 2106-07-0021 to J.W.), an Ole Rømer grant from the Danish Natural Science Research Council and the Solexa project (272-07-0196 to J.W.), the Fund for Science and Technology Development (FDCT) from Macao (grant 077/2014/A2 to J.W.) and the Research Special Fund for Public Welfare Industry of Health (grant 2013202017 to X.Z.). The authors are very grateful to colleagues at BGI-Shenzhen for DNA extraction, library construction, sequencing and discussions.

Author information

Author notes

    • Xuan Zhang
    • , Dongya Zhang
    • , Huijue Jia
    • , Qiang Feng
    • , Donghui Wang
    •  & Di Liang

    These authors contributed equally to this work.

Affiliations

  1. Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

    • Xuan Zhang
    • , Di Liang
    • , Xiangni Wu
    • , Hua Chen
    • , Li Wang
    • , Qing-jun Wu
    • , Fengchun Zhang
    • , Wenjie Zheng
    •  & Yongzhe Li
  2. BGI-Shenzhen, Shenzhen, China.

    • Dongya Zhang
    • , Huijue Jia
    • , Qiang Feng
    • , Donghui Wang
    • , Junhua Li
    • , Longqing Tang
    • , Yin Li
    • , Zhou Lan
    • , Bing Chen
    • , Yanli Li
    • , Huanzi Zhong
    • , Hailiang Xie
    • , Zhuye Jie
    • , Weineng Chen
    • , Shanmei Tang
    • , Xiaoqiang Xu
    • , Xiaokai Wang
    • , Xianghang Cai
    • , Sheng Liu
    • , Yan Xia
    • , Jiyang Li
    • , Jumana Yousuf Al-Aama
    • , Mingrong Zhang
    • , Guangwen Luo
    • , Wenbin Xue
    • , Liang Xiao
    • , Jun Li
    • , Wanting Chen
    • , Xun Xu
    • , Ye Yin
    • , Huanming Yang
    • , Jian Wang
    • , Karsten Kristiansen
    • , Yingrui Li
    •  & Jun Wang
  3. Shenzhen Key Laboratory of Human Commensal Microorganisms and Health Research, BGI-Shenzhen, Shenzhen, China.

    • Dongya Zhang
    • , Huijue Jia
    • , Junhua Li
    •  & Liang Xiao
  4. Shenzhen Engineering Laboratory of Detection and Intervention of Human Intestinal Microbiome, BGI-Shenzhen, Shenzhen, China.

    • Qiang Feng
  5. Department of Biology, University of Copenhagen, Copenhagen, Denmark.

    • Qiang Feng
    • , Donghui Wang
    • , Karsten Kristiansen
    •  & Jun Wang
  6. School of Bioscience and Biotechnology, South China University of Technology, Guangzhou, China.

    • Junhua Li
  7. BGI Education Center, University of Chinese Academy of Sciences, Shenzhen, China.

    • Xiaoqiang Xu
    • , Xiaokai Wang
    • , Sheng Liu
    •  & Yan Xia
  8. Qingdao University–BGI Joint Innovation College, Qingdao University, Qingdao, China.

    • Jiyang Li
  9. Department of Mathematical Sciences, Binghamton University, State University of New York, Binghamton, New York, USA.

    • Xingye Qiao
  10. Princess Al-Jawhara Al Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.

    • Jumana Yousuf Al-Aama
  11. Macau University of Science and Technology, Taipa, Macau, China.

    • Liang Liu
    • , Ting Li
    •  & Jun Wang
  12. Department of Rheumatology, Guangdong Hospital of Traditional Chinese Medicine, Guangzhou, China.

    • Qingchun Huang

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Contributions

X.Z., Yingrui Li and Jun Wang conceived and directed the project. X.Z., D.L., X. Wu, H.C., L.W., Q.-j.W., F.Z., W.Z. and Yongzhe Li made clinical diagnoses and performed treatment and sample collection. Z.L. and M.Z. managed the samples at BGI. D.Z., H.J., Q.F., D.W., Z.J., L.T., Yin Li, B.C., Z.L., Yanli Li, H.X., Junhua Li, Weineng Chen, S.T., Xiaoqiang Xu, X. Wang, X.C., S.L., Y.X., Jiyang Li and H.Z. performed bioinformatic analyses. X.Z., H.J. and L.L. wrote the manuscript. X.Q., G.L., W.X., L.X., Jun Li, Wanting Chen, Xun Xu, Y.Y., H.Y., Jian Wang, J.Y.A., K.K., T.L. and Q.H. contributed to data collection and text revision.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Xuan Zhang or Yingrui Li or Jun Wang.

Supplementary information

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DOI

https://doi.org/10.1038/nm.3914

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