Background/Purpose: Although various genetic factors have been implicated in susceptibility to rheumatoid arthritis (RA), environmental factors including smoking, periodontal disease and hormones are also necessary for the disease manifestations. We speculate that gut microbiota is one such environmental factor that may be correlated with the development of RA. Previous reports have demonstrated that RA patients have altered composition of gut microbiota. However, it remains unclear whether the altered composition of intestinal microbiota observed in RA patients causes the disease onset.

Methods: We first examined whether RA patients have particular patterns of microbiota. All the patients were diagnosed according to the American College of Rheumatology/European League Against Rheumatism 2010 classification criteria for RA. We collected human fecal samples from 17 untreated new-onset RA patients (disease duration 1.0±0.7 years, mean±SD) and 13 healthy volunteers to investigate the microbiota by 16S rRNA-based deep sequence technique. We further analyzed the correlation between bacterial counts of intestinal microbiota and disease activity in 50 treated RA patients (disease duration 9.6±9.0 years, mean±SD) by quantitative reverse transcription PCR (RT-qPCR) method. We also inoculated human fecal samples from new-onset RA patients or healthy controls into germ free SKG mice (intestinal microbiota-humanized mice) and analyzed for the severity of arthritis and immune responses. We next evaluated whether Prevotella copri (P. copri) has an ability to induce Th17-related cytokines in vitro. Bone marrow-derived DCs were stimulated with intestinal bacteria and analyzed for the production of Th17-related cytokines. Finally, we inoculated P. copri into germ free SKG mice and analyzed severity of arthritis.

Results: Six out of 17 new-onset RA patients showed high abundance of Prevotella. Especially, P. copri was dominant OTU in the RA patients. None of the healthy controls harbored increased abundance of Prevotella. The bacterial counts of Prevotella were positively correlated with the disease activity of treated 50 RA patients (r = 0.36, P<0.01). SKG mice harboring Prevotella-dominated microbiota from new-onset RA patients (RA-SKG mice) showed severe arthritis in the presence of zymosan injection. Increased number of Th17 cells in the regional lymph nodes and large intestine was observed in RA-SKG mice. P. copri induced high production of IL-6 and IL-23, indicating that P.copri has an ability to enhance Th17-biased immune responses. Mono-colonization of P. copri into germ free SKG mice also showed arthritis.

Conclusion: Prevotella–dominated gut microbiota may contribute to the development of arthritis both in human RA patients and SKG mice.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-analysis-of-severity-of-arthritis-in-the-intestinal-microbiota-humanized-mice/