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

Abstract

Background Porphyromonas 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. Methods Pg 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. Results Periodontal 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. Conclusion Pg oral infection affected gut microbiota dysbiosis and joint destruction via increased CP generation.

Periodontal pathogens alter the synovial proteome. Periodontal pathogens do not exacerbate macroscopic arthritis but alter the synovial proteome in mice

“…Indeed, timing may play a role here as previous publications demonstrating an exacerbation of arthritis through periodontal disease opted for shorter time lapses between inductions of both diseases [ 37 – 39 ]. More differences may arise from the use of various mouse strains, different modes to induce arthritis to the point of collagen type II derived from chicken vs cow [ 29 , 40 ]. In our experiments, the sums of arthritis scores at endpoint were higher for those mice that were subjected to CIA first however, we attribute this difference to different disease durations.…”

Exploring the Oral Microbiome in Rheumatic Diseases, State of Art and Future Prospective in Personalized Medicine with an AI Approach

“…Oral microbiota seems to have a crucial role not only in RA pathogenesis but also in exacerbation of joint involvement and in treatment response. In fact, it has been shown that dysbiosis may exacerbate arthritis through the oral inoculation of P. gingvalis using animal models, even if the mechanism underlying the exacerbation is not entirely elucidated [ 49 ]. In a collagen-type II experimental arthritis in mice, periodontitis caused by P. gingivalis and Provotellanigrescens exacerbated arthritis through TLR2-dependent antigen-specific Th17 immune response [ 49 ].…”

Multifaceted Impacts of Periodontal Pathogens in Disorders of the Intestinal Barrier

“…Therefore, it is questioned whether PPAD synthesized by P. gingivalis influences the progression of RA (129)(130)(131). A hypothesis was proposed that immune responses in the gut that were elicited with P. gingivalis inoculation exacerbated RA (132). T helper 17 (Th17) cells have been proven to be involved in the progression of RA by regulating the adaptive immune response, particularly at mucosal surfaces in the intestine (133).…”