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The positive correlation between Porphyromonas gingivalis and Prevotella spp. Response to: ‘Comment on ‘Metagenome-wide association study of gut microbiome revealed novel aetiology of rheumatoid arthritis in the Japanese population’ by Kishikawa et al.’ by Kitamura et al
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  1. Toshihiro Kishikawa1,2,
  2. Yuichi Maeda3,4,
  3. Takuro Nii3,4,
  4. Yukinori Okada1,5,6
  1. 1Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan
  2. 2Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Suita, Japan
  3. 3Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan
  4. 4Laboratory of Immune Regulation, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Suita, Japan
  5. 5Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan
  6. 6Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan
  1. Correspondence to Dr Yukinori Okada, Department of Statistical Genetics, Osaka Shiritsu Daigaku Daigakuin Igaku Kenkyuka Igakubu, Osaka 565-0871, Japan; yokada{at}sg.med.osaka-u.ac.jp

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We thank Kitamura et al. for their interest in our study and for providing their thoughts through correspondence.1 They reported interesting characteristics of Porphyromonas gingivalis (Pg) regarding rheumatoid arthritis (RA) as follows: (1) oral infection of Pg increased serum levels of lipopolysaccharide (LPS)2 3; (2) oral administration of Pg decreased the proportion of phylum Bacteroidetes3; and (3) serum LPS levels were inversely associated with Bacteroides counts. In our metagenome-wide association study (MWAS) of the RA gut microbiome,4 5 we had identified high abundances of five species belonging to the genus Prevotella (i.e., P. denticola, P. marshii, P. disiens, P. corporis, and P. amnii) in the RA metagenome. Considering that Prevotella in the RA gut microbiome showed an inverse relationship with Bacteroides,6 7 disentanglement of gut microbiome link between Pg and the Prevotella spp. should be of interest.

In our RA MWAS, we had excluded Pg from the analysis because the average relative abundance of Pg was below the quality control threshold of 0.001%. Here, we additionally examined the case–control association test of Pg and found no significant association (P = 0.78). However, we found significant positive correlations of the relative abundance between Pg and three of the RA-associated five Prevotella species (i.e., P. denticola, P. corporis and P. amnii; P < 0.017; figure 1A). When we focused on the total abundance of the five Prevotella species, significant positive correlation was also found (r = 0.291, P = 0.0011). This result suggests that Pg and the Prevotella spp. in the RA gut microbiome cooperate in the RA pathophysiology.

Figure 1

Characteristics of Porphyromonas gingivalis (Pg) in the rheumatoid arthritis (RA) gut microbiome. (A) Correlation between the relative abundance of Pg and that of Prevotella spp. The x-axes indicate the relative abundance of Pg in a logarithmic scale. The y-axes indicate the relative abundance of each of the five Prevotella species with significant RA-control discrepancy (ie, P. denticola, P. marshii, P. disiens, P. corporis, and P. amnii) and the total abundance of the five Prevotella spp. in a logarithmic scale. (B) Correlations between the relative abundance of the taxa and RA activity indices and biomarkers. Only correlations with p values less than 0.05 were coloured (positive correlations in red and negative correlations in blue). Wilcoxon rank-sum tests were used to compare the high-level and low-level groups. Stage indicates Steinbrocker classification of the joint X-rays. RF, rheumatoid factor; ACPA, anti-citrullinated peptide antibody; DAS28CRP, Disease Activity Score 28-joint count C reactive protein.

Another concern by Kitamura et al. was the distinct distributions of the RA prognostic factors between the RA case groups with high and low abundance in the Prevotella spp or Pg. They reported that serum LPS-binding protein was positively correlated with activity indices and biomarkers of RA (e.g., Disease Activity Score 28-joint count C reactive protein (DAS28CRP), CRP, rheumatoid factor (RF) and anti-citrullinated peptide antibody (ACPA)).1 We assessed whether the relative abundance of the Prevotella spp and Pg showed the correlation with RF, ACPA, DAS28-CRP and the Steinbrocker stage. As for RF and ACPA, the RA cases were compared between the high-level and low-level groups stratified according to the threshold of 15 and 4.5 IU/mL, respectively. While Prevotella corporis had nominally significant positive correlation with ACPA (fold change = 3.18, P = 0.0098), most of the correlations were not significant (figure 1B). In our study samples, we did not observe positive correlation of the five Prevotella spp. and Pg with RA activity indices and biomarkers.

In conclusion, our study suggests that Pg and the Prevotella spp. cooperate in the RA gut microbiome. Further studies focusing on the interaction of these two taxa are warranted to elucidate RA aetiology.

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Footnotes

  • Handling editor Josef S Smolen

  • Contributors TK and YO designed the study, conducted the data analysis and wrote the manuscript. YM and TN conducted the experiments collected the samples. YO supervised the study.

  • 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.

  • Patient consent for publication Not required.

  • Provenance and peer review Commissioned; internally peer reviewed.

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