Periodontal treatment prevents arthritis in mice and methotrexate ameliorates periodontal bone loss

Paul M Lübcke,Hermann Lang,Johann Volzke,Bernd Kreikemeyer,Brigitte Müller-Hilke,Meinolf N B Ebbers,Jana Bull,Robby Engelmann,Susanne Kneitz

doi:10.1038/s41598-019-44512-9

Abstract

Recent studies indicate a causal relationship between the periodontal pathogen P. gingivalis and rheumatoid arthritis involving the production of autoantibodies against citrullinated peptides. We therefore postulated that therapeutic eradication P. gingivalis may ameliorate rheumatoid arthritis development and here turned to a mouse model in order to challenge our hypothesis. F1 (DBA/1 x B10.Q) mice were orally inoculated with P. gingivalis before collagen-induced arthritis was provoked. Chlorhexidine or metronidazole were orally administered either before or during the induction phase of arthritis and their effects on arthritis progression and alveolar bone loss were compared to intraperitoneally injected methotrexate. Arthritis incidence and severity were macroscopically scored and alveolar bone loss was evaluated via microcomputed tomography. Serum antibody titres against P. gingivalis were quantified by ELISA and microbial dysbiosis following oral inoculation was monitored in stool samples via microbiome analyses. Both, oral chlorhexidine and metronidazole reduced the incidence and ameliorated the severity of collagen-induced arthritis comparable to methotrexate. Likewise, all three therapies attenuated alveolar bone loss. Relative abundance of Porphyromonadaceae was increased after oral inoculation with P. gingivalis and decreased after treatment. This is the first study to describe beneficial effects of non-surgical periodontal treatment on collagen-induced arthritis in mice and suggests that mouthwash with chlorhexidine or metronidazole may also be beneficial for patients with rheumatoid arthritis and a coexisting periodontitis. Methotrexate ameliorated periodontitis in mice, further raising the possibility that methotrexate may also positively impact on the tooth supporting tissues of patients with rheumatoid arthritis.

Highlights

Rheumatoid arthritis (RA) and periodontitis (PD) are frequent chronic inflammatory diseases
Candidate antigens like bacterial enolase, that displays 80% homology to human enolase, may serve as initial targets for an immune response that via molecular mimicry and epitope spreading will eventually turn against self[22,23]. This scenario was supported by the finding that the ability of P. gingivalis to augment collagen-induced arthritis (CIA) in mice was dependent on the expression PPAD24,25
We initially postulated that antimicrobial therapy after P. gingivalis induced periodontitis would ameliorate subsequent CIA development

Summary

Introduction

Rheumatoid arthritis (RA) and periodontitis (PD) are frequent chronic inflammatory diseases. Candidate antigens like bacterial enolase, that displays 80% homology to human enolase, may serve as initial targets for an immune response that via molecular mimicry and epitope spreading will eventually turn against self[22,23]. This scenario was supported by the finding that the ability of P. gingivalis to augment collagen-induced arthritis (CIA) in mice was dependent on the expression PPAD24,25. We induced collagen induced-arthritis (CIA), one of the most widely used animal models for RA28,29 and subsequently subjected the mice to various therapy regimen against either of these diseases. In order to monitor microbial dysbiosis following oral inoculation, arthritis induction and subsequent bacterial eradication, we monitored the gut microbiome over the course of the experiment

Methods

Results

Conclusion