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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.
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.
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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