ObjectivesPrevotella copriis considered to be a contributing factor in rheumatoid arthritis (RA). However, in some non-Westernised countries, healthy individuals also harbour an abundance ofP. copriin the intestine. This study investigated the pathogenicity of RA patient-derivedP. copri(P. copri_RA) compared with healthy control-derivedP. copri(P. copri_HC).MethodsWe obtained 13P.copristrains from the faeces of patients with RA and healthy controls. Following whole genome sequencing, the sequences ofP. copri_RAandP. copri_HCwere compared. To analyse the arthritis-inducing ability ofP. copri, we examined two arthritis models (1) a collagen-induced arthritis model harbouringP. copriunder specific-pathogen-free conditions and (2) an SKG mouse arthritis model underP. copri-monocolonised conditions. Finally, to evaluate the ability ofP. coprito activate innate immune cells, we performed in vitro stimulation of bone marrow-derived dendritic cells (BMDCs) byP. copri_RAandP. copri_HC.ResultsComparative genomic analysis revealed no apparent differences in the core gene contents betweenP. copri_RAandP. copri_HC, but pangenome analysis revealed the high genome plasticity ofP. copri. We identified aP. copri_RA-specific genomic region as a conjugative transposon. In both arthritis models,P. copri_RA-induced more severe arthritis thanP. copri_HC. In vitro BMDC stimulation experiments revealed the upregulation of IL-17 and Th17-related cytokines (IL-6, IL-23) byP. copri_RA.ConclusionOur findings reveal the genetic diversity ofP. copri, and the genomic signatures associated with strong arthritis-inducing ability ofP. copri_RA. Our study contributes towards elucidation of the complex pathogenesis of RA.