Genomic repertoires linked with pathogenic potency of arthritogenicPrevotella copriisolated from the gut of patients with rheumatoid arthritis

Abstract

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. copriRA) compared with healthy control-derivedP. copri(P. copriHC).MethodsWe obtained 13P.copristrains from the faeces of patients with RA and healthy controls. Following whole genome sequencing, the sequences ofP. copriRAandP. copriHCwere 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. copriRAandP. copriHC.ResultsComparative genomic analysis revealed no apparent differences in the core gene contents betweenP. copriRAandP. copriHC, but pangenome analysis revealed the high genome plasticity ofP. copri. We identified aP. copriRA-specific genomic region as a conjugative transposon. In both arthritis models,P. copriRA-induced more severe arthritis thanP. copriHC. In vitro BMDC stimulation experiments revealed the upregulation of IL-17 and Th17-related cytokines (IL-6, IL-23) byP. copriRA.ConclusionOur findings reveal the genetic diversity ofP. copri, and the genomic signatures associated with strong arthritis-inducing ability ofP. copriRA. Our study contributes towards elucidation of the complex pathogenesis of RA.