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Shotgun metagenomics reveals an enrichment of potentially cross-reactive bacterial epitopes in ankylosing spondylitis patients, as well as the effects of TNFi therapy upon microbiome composition
  1. Jian Yin1,
  2. Peter Richard Sternes2,
  3. Mingbang Wang3,
  4. Jing Song1,
  5. Mark Morrison4,
  6. Ting Li1,
  7. Ling Zhou1,
  8. Xin Wu1,
  9. Fusheng He5,
  10. Jian Zhu6,
  11. Matthew A Brown2,
  12. Huji Xu1,6,7
  1. 1Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, China
  2. 2Translational Genomics Group, Institute of Health and Biomedical Innovation, Brisbane, Queensland, Australia
  3. 3Shanghai Key Laboratory of Birth Defects, Children’s Hospital of Fudan University, Shanghai, China
  4. 4University of Queensland Diamantina Institute, Brisbane, Queensland, Australia
  5. 5Imunobio, Shenzhen, China
  6. 6Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
  7. 7Peking-Tsinghua Center for Life Sciences, Tsinghua University, Beijing, China
  1. Correspondence to Professor Matthew A Brown, Guy’s & St Thomas’ NHS Foundation Trust and King’s College London NIHR Biomedical Research Centre, Guy’s Hospital, London, UK; matt.brown{at}; Professor Huji Xu, Beijing Tsinghua Changgeng Hospital School of Clinical Medicine Tsinghua University, Beijing 100084, China; huji_xu{at}


Objectives Diverse evidence including clinical, genetic and microbiome studies support a major role of the gut microbiome in the common immune-mediated arthropathy, ankylosing spondylitis (AS). We set out to (1) further define the key microbial characteristics driving disease, and (2) examine the effects of tumour necrosis factor-inhibitor (TNFi) therapy upon the microbiome.

Methods The stools from a case–control cohort of 250 Han-Chinese subjects underwent shotgun metagenomic sequencing. All subjects were genotyped using the Illumina CoreExome SNP microarray.

Results Previous reports of gut dysbiosis in AS were reconfirmed and several notable bacterial species and functional categories were differentially abundant. TNFi therapy was correlated with a restoration the perturbed microbiome observed in untreated AS cases to that of healthy controls, including several important bacterial species that have been previously associated with AS and other related diseases. Enrichment of bacterial peptides homologous to HLA-B27-presented epitopes was observed in the stools of patients with AS, suggesting that either HLA-B27 fails to clear these or that they are involved in driving HLA-B27-associated immune reactions. TNFi therapy largely restored the perturbed microbiome observed in untreated AS cases to that of healthy controls, including several important bacterial species that have been previously associated with AS and other related diseases. TNFi therapy of patients with AS was also associated with a reduction of potentially arthritogenic bacterial peptides, relative to untreated patients.

Conclusion These findings emphasise the key role that the gut microbiome plays in driving the pathogenesis of AS and highlight potential therapeutic and/or preventative targets.

  • Ankylosing Spondylitis
  • Anti-TNF
  • Spondyloarthritis
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  • Handling editor Josef S Smolen

  • JY and PRS contributed equally.

  • MAB and HX contributed equally.

  • Correction notice This article has been corrected since it published Online First. The second corresponding author has been added and affiliation 7 has been updated.

  • Contributors Study design was performed by HX, JY and MAB. Subject recruitment and sample collection was performed by JY, JS, TL, LZ, XW and JZ. Metagenomic analysis was performed by PRS, and bacterial epitope studies by JY, FH and MW. The manuscript was prepared by PRS, MM, MAB and HX.

  • Funding HX is supported by National Science Foundation of China (Grant 81430031) and China Ministry of Science and technology (973 Program of China 2014CB541800). MAB is funded by a National Health and Medical Research Council Senior Principal Research Fellowship (#1024879).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval All human studies have been approved by the Research Ethical Committee of Second Military Medical University, and all patients and controls gave informed written consent for their participation in the studies.

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

  • Data availability statement Data are available upon reasonable request.

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