Effect of Porphyromonas gingivalis infection on gut dysbiosis and resultant arthritis exacerbation in mouse model

Arthritis Research & Therapy

Jyunzo Hisatsune¹  Shintaro Hirata²  Eiji Sugiyama²  Tatsuhiko Ozawa³  Hiroyuki Kishi³  Koji Nakayama⁴  Mikio Shoji⁴  Kotaro Tanimoto⁵  Isamu Kado⁵  Shinji Matsuda⁶  Tsuyoshi Fujita⁶  Syuichi Munenaga⁶  Noriyoshi Mizuno⁶  Mikihito Kajiya⁶  Hidemi Kurihara⁶  Kazuhisa Ouhara⁶  Yuta Hamamoto⁶  Toshihisa Kawai⁷ 

[1] Antimicrobial Resistance Research Center, National Institute of Infectious Diseases (NIID), Toyama 1-23-1, Shinjuku-ku, 162-8640, Tokyo, Japan;Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, 734-8551, Hiroshima, Japan;Department of Immunology, Faculty of Medicine, Academic Assembly, University of Toyama, 2630 Sugitani, 930-0194, Toyama, Japan;Department of Microbiology and Oral Infection, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, 852-8588, Nagasaki, Japan;Department of Orthodontics and Craniofacial Developmental Biology, Graduate School of Biomedical & Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8553, Hiroshima, Japan;Department of Periodontal Medicine, Division of Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8553, Hiroshima, Japan;Department of Periodontology, Nova Southeastern University College of Dental Medicine, 3200 South University Drive, 33328, Fort Lauderdale, FL, USA;

关键词: Porphyromonas gingivalis;    Rheumatoid arthritis;    Periodontitis;    Citrullinated protein;    Dysbiosis;   

DOI  :  10.1186/s13075-020-02348-z

来源: Springer

【 摘 要 】

BackgroundPorphyromonas gingivalis (Pg) infection causes periodontal disease and exacerbates rheumatoid arthritis (RA). It is reported that inoculation of periodontopathogenic bacteria (i.e., Pg) can alter gut microbiota composition in the animal models. Gut microbiota dysbiosis in human has shown strong associations with systemic diseases, including RA, diabetes mellitus, and inflammatory bowel disease. Therefore, this study investigated dysbiosis-mediated arthritis by Pg oral inoculation in an experimental arthritis model mouse.MethodsPg inoculation in the oral cavity twice a week for 6 weeks was performed to induce periodontitis in SKG mice. Concomitantly, a single intraperitoneal (i.p.) injection of laminarin (LA) was administered to induce experimental arthritis (Pg-LA mouse). Citrullinated protein (CP) and IL-6 levels in serum as well as periodontal, intestinal, and joint tissues were measured by ELISA. Gut microbiota composition was determined by pyrosequencing the 16 s ribosomal RNA genes after DNA purification of mouse feces. Fecal microbiota transplantation (FMT) was performed by transferring Pg-LA-derived feces to normal SKG mice. The effects of Pg peptidylarginine deiminase (PgPAD) on the level of citrullinated proteins and arthritis progression were determined using a PgPAD knockout mutant.ResultsPeriodontal alveolar bone loss and IL-6 in gingival tissue were induced by Pg oral infection, as well as severe joint destruction, increased arthritis scores (AS), and both IL-6 and CP productions in serum, joint, and intestinal tissues. Distribution of Deferribacteres and S24-7 was decreased, while CP was significantly increased in gingiva, joint, and intestinal tissues of Pg-inoculated experimental arthritis mice compared to experimental arthritis mice without Pg inoculation. Further, FMT from Pg-inoculated experimental arthritis mice reproduced donor gut microbiota and resulted in severe joint destruction with increased IL-6 and CP production in joint and intestinal tissues. The average AS of FMT from Pg-inoculated experimental arthritis was much higher than that of donor mouse. However, inoculation of the PgPAD knockout mutant inhibited the elevation of arthritis scores and ACPA level in serum and reduced CP amount in gingival, joint, and intestinal tissues compared to Pg wild-type inoculation.ConclusionPg oral infection affected gut microbiota dysbiosis and joint destruction via increased CP generation.

【 授权许可】

CC BY