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We thank Liu et al for their interest in our paper and for providing their thoughts through correspondence.1 We agree that gut microbiome studies are promising to identify novel insights into the sexual dimorphism in rheumatoid arthritis (RA). We reported that the genus of Gardnerella and the species of Gardnerella vaginalis increased in the gut microbiome of patients with RA.2 G. vaginalis is known as a representative causal bacterium of vaginosis. In our study, G. vaginalis was detected in both male and female samples, and there were no significant gender differences in their relative abundance (P=0.41). Thus, the increment of G. vaginalis was less likely to be contamination from the female genital organ in perineum. We further performed case-control association tests of G. vaginalis stratified by gender with age, sequencing groups and the top two principal components as covariates (figure 1A). We found that the effect size was larger in female samples (beta=1.14, P=4.1×10-4) than in male samples (beta=0.596, P=0.22). This result suggests that the increment of Gardnerella in the gut microbiome of patients with RA is specific to the female samples.
Gardnerella has been detected not only in vaginitis but also in a variety of infections, such as hip arthritis and joint infections.3 However, their biological and pathological roles in gut microbiome have been elusive. G. vaginalis was reported to have a symbiotic positive relationship with Prevotella bivia.4 Considering the association of Prevotella with RA aetiology,5–7 Liu et al proposed that G. vaginalis affects RA aetiology through the symbiotic proliferation of Prevotella. In our study, there was no significant positive correlation between the relative abundance of the genus Prevotella and that of G. vaginalis (r=0.054, P=0.47; figure 1B). However, when we focused on the total abundance of the five Prevotella species with significant RA-control discrepancy (i.e., P. denticola, P. marshii, P. disiens, P. corporis and P. amnii), significant positive correlation was found (r=0.20, P=0.024). Among the five RA-associated species, P. amnii had nominally significant positive correlation (r=0.19, P=0.035) with G. vaginalis, while the others did not (P>0.062). There was no significant correlation between P. bivia and G. vaginalis either (P=0.84). These results demonstrated that Gardnerella and RA-associated Prevotella had a symbiotic relationship in gut microbiome. Further studies are required to reveal the role of the G. vaginalis in the gut microbiome of patients with RA.
Liu et al also mentioned that female patients with RA confer more severe inflammation profiles (i.e., 28-joint Disease Activity Score (DAS28)) than male patients.8 Assessing whether Gardnerella is responsible for the sexual difference of RA severity, we performed association tests between the relative abundance of G. vaginalis and DAS28-CRP, but no significant association was found (P=0.91, r=−0.013). This result indicates that Gardnerella in gut microbiome may not be related to RA severity in female samples.
We hoped that researches focusing on G. vaginalis would lead to further clarification of aetiology of RA.
Patient consent for publication
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 and 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.
Provenance and peer review Commissioned; internally peer reviewed.
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