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Comment on: ‘Metagenome-wide association study of gut microbiome revealed novel aetiology of rheumatoid arthritis in the Japanese population’ by Kishikawa et al
  1. Kaori Kitamura1,
  2. Hiroshi Shionoya1,
  3. Kuniaki Terato2,
  4. Suguru Suzuki1,
  5. Richio Fukai3,
  6. Shinichi Uda4,
  7. Chiyuki Abe5,
  8. Hiromitsu Takemori6,
  9. Keita Nishimura7,
  10. Hisashi Baba8,
  11. Takaki Waritani2,
  12. Kou Katayama9
  1. 1 Research Lab Section 5, Asama Chemical Co Ltd, Tokyo, Japan
  2. 2 Research and Development, Chondrex, Inc, Redmond, Washington, USA
  3. 3 Pharmacology, Fukai Pharmacy, Asahikawa, Hokkaido, Japan
  4. 4 Rheumatology, Uda Clinic of Rheumatology, Fukuyama, Hiroshima, Japan
  5. 5 Rheumatology, Abe Clinic Internal Medicine, Tokyo, Japan
  6. 6 Rheumatology, Aomori Prefectural Central Hospital, Aomori, Aomori, Japan
  7. 7 Rheumatology, Teikyo University School of Medicine, Tokyo, Japan
  8. 8 Company Rheu・Con, Osaka, Japan
  9. 9 Rheumatology, Katayama Orthopedic Rheumatology Clinic, Asahikawa, Hokkaido, Japan
  1. Correspondence to Dr Kou Katayama, Rheumatology, Katayama Orthopedic Rheumatology Clinic, Asahikawa, Hokkaido 078-8243, Japan; kou{at}

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The recent paper from Kishikawa et al 1 provides an extremely important new insight on the concept of oral-gut microbiome axis and rheumatoid arthritis (RA) pathogenesis.

Alterations in the gut microbiome at mucosal sites have been implicated in the pathogenesis of RA.2–4 Increasing evidence suggests a link between RA and periodontal infections caused by Porphyromonas gingivalis (Pg).5 Oral infection by Pg in an animal model revealed increased serum levels of lipopolysaccharide (LPS), dysbiosis and aggravation of arthritis.6 7 Therefore, the pathogenesis of RA is considered to be associated with the immunomodulatory activity of oral and gut microbiome.8 However, few studies have explored the relationship between the oral-gut microbiome axis and RA pathogenesis.

We previously investigated the relationship between RA disease activity using activity indices and biomarkers; the total bacterial counts and the counts of five well-known gut bacteria species; LPS-related biomarkers and IgG and IgA anti-Pg-LPS antibodies in 87 patients with established RA showing inadequate responses to conventional synthetic disease-modifying antirheumatic drugs or exhibiting severe complications.9 (online supplementary table 1)

Little significant relationship was observed between the counts of the total bacteria, five species of bacteria and activity indices and biomarkers.(table 1) The levels of LPS-related biomarkers, particularly serum LPS-binding protein (LBP), were positively correlated with activity indices and biomarkers, suggesting that bacterial LPS-LBP complexes from the gut microbiome may activate nuclear factor κB via toll-like receptor 4 and may initiate and perpetuate inflammation10 11 in established RA.

Table 1

Relationships between RA activity indices, disease biomarkers, gut bacterial counts, LPS-related biomarkers and IgG and IgA anti-Pg LPS antibodies in 87 patients with RA.

IgA antibody responses against Pg-LPS, were inversely correlated with the counts of intestinal bacteria, affecting the microbiome balance, and showed a positive correlation with serum LPS and LBP levels, suggesting barrier damage due to intestinal infection with Pg. These results support previous findings in collagen-induced arthritis models showing that oral administration of Pg significantly affected the gut barrier function and the gut microbiota composition, specifically by decreasing the proportion of phylum Bacteroidetes, increasing the proportion of phylum Firmicutes. 7

Furthermore, IgG anti-Pg-LPS antibody levels, which are indicative of systemic infection, are inversely correlated with RA activity indices; these results are comparable to those of our previous study of destructive RA.12 Thus, these results demonstrate that the oral-gut microbiome axis relationship may aggravate disease activity in RA.

Kishikawa et al recently performed a genome-wide association study to analyse the role of the gut microbiome in RA; they compared 82 Japanese patients with early RA with 42 age-matched and sex-matched normal controls1 (online supplementary table 1).

In this study, faecal samples were subjected to whole-genome shotgun sequencing. Case–control phylogenetic association analyses, conducted using a generalised linear regression model, showed that multiple species belonging to the Prevotella genus increased in the RA gut metagenome. Multiple Prevotella spp., in addition to Prevotella copri, which was recently identified by shotgun sequencing, have been identified in the oral cavity. It has been speculated that colonisation of the intestine by oral bacteria is related to the pathogenesis of RA and other diseases suggesting existence of oral-gut microbiome axis relationship.

In Kishikawa’s study, a representative finding was decreased expression of the redox reaction-related gene R6FCZ7 which is involved in oxidative stress in the genus Bacteroides in RA than in healthy subjects. It was previously reported that the counts of Prevotella and Bacteroides in the gut in RA show an inverse relationship.3 They suggested that R6FCZ7 and the genus Prevotella are inversely associated via the relationship with the genus Bacteroides. In our study, levels of serum LPS, a potent generator of reactive oxygen species,10 as well as IgA anti-Pg-LPS antibody levels, which indicate gut infection with Pg, are inversely associated with Bacteroides counts. Both studies showed that the key gene R6FCZ7 and LPS are associated with the generation of reactive oxygen species and are regulated by the balance of gut bacteria, including oral bacteria.

From the viewpoint of clinical application, we have questions to authors after comparison with two studies discussing two oral origin microbiome; Prevotella spp. and Pg.

Prevotella copri was most abundant in patients with new-onset RA3 4 suggesting its pathogenic role. Moreover, Maeda et al reported SKG mice harbouring microbiota dominated by P. copri from early RA patients had an increased number of intestinal Th17 cells and developed destructive arthritis when treated with zymosan.4 Another microbiome from oral cavity, Pg is also considered to play a pathogenic role in RA since Pg peptidylarginine deiminase is implicated in the autoimmunity of RA by creating mimic antigen, circular citrullinated peptide (CCP), by autocitrullination.5 Interestingly, anti-Pg-LPS antibody associated with RA clinical indices and biomarker in our study with established RA, suggesting the role for continuation of RA inflammation.9 These data by Maeda and ours might show the possibility that multiple Prevotella spp. other than P. copri or Pg play not only pathogenic but prognostic role. Were there significant differences of values in prognostic factors (rheumatoid factor, anti-CCP antibody, matrix metalloproteinase 3, HLA-DRB1 gene, bone erosion and so on) between high and low abundant groups in multiple Prevotella spp. or Pg? ; results from such analyses would have provided crucial information for understanding of RA pathogenesis.

Overall, our findings and those of others suggest that modulation of the oral-gut microbiome axis is a promising strategy for the treatment and management of RA.

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The authors thank our colleagues Jessica Chang and Bonnie McKinney for reviewing and proofreading this manuscript. The authors thank Kiyomi Kamiya for assistance for patients’ data collection.



  • KK, HS, KT, SS and KK contributed equally.

  • Contributors HS, KoK and KT designed basic study plans, acquired, analysed and interpreted the data. KoK, KaK, HS, HB and KT drafted this manuscript. KaK, SS conducted most of the analysis in this study including faecal bacteria and LPS-related biomarker analysis. KoK, SU, CA, HT and KN conducted the clinical study with their patients. TW confirmed data by conducting related, but independent experiments, interpreted data and contributed to the preparation of this manuscript. RF conducted the statistical analysis and interpreted the data based on statistical significance. All authors have read and approved of the final manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • 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; internally 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.

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