Mucosal innate immune activation as the trigger to Prevotella species-induced arthritis in genetically resistant mice

An altered gut microbiota, particularly the expansion of Prevotellaceae members, is implicated in the pathogenesis of rheumatoid arthritis (RA), yet the mechanisms behind this phenomenon remain unclear. Here, we demonstrate that Palleniella intestinalis, a member of the Prevotellaceae family, induces 100% of arthritis incidence in genetically resistant C57BL/6 mice. Inoculation with P. intestinalis modifies gut microbiota ecology, increases intestinal permeability, and selectively activates colonic CD11b⁺CD11c⁺ myeloid cells, facilitating T helper 17 (Th17) differentiation and driving joint inflammation. In vitro, outer membrane vesicles (OMVs) from P. intestinalis and Segatella copri (formerly known as Prevotella copri) prime bone marrow-derived dendritic cells (BMDCs) to drive Th17 differentiation in an interleukin-6 (IL-6)-dependent manner. Similar innate immune activation with elevated IL-6 levels was observed in gut biopsies from new-onset patients with RA. Transfer of Prevotellaceae-derived OMVs or Prevotellaeae-primed BMDCs replicates the heightened arthritis incidence in resistant mice, highlighting the critical role of intestinal immune activation in RA.