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 increasingly implicated in the pathogenesis of rheumatoid arthritis (RA), yet the mechanisms hind this phenomenon remain unclear. Here, we demonstrate that Palleniella intestinalis , a member of the Prevotellaceae family, induces a 100% 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 Th17 differentiation and driving joint inflammation. In vitro , outer membrane vesicles (OMV) from P. intestinalis and Segatella copri (formerly known as Prevotella copri ) prime bone marrow-derived dendritic cells (BMDCs) to drive Th17 differentiation in an IL-6-dependent manner. Similar changes with increase in innate immune cell activation and IL-6 levels were shown in gut biopsies from new-onset RA patients. The transfer of Prevotellaceae -derived OMVs or Prevotellaeae -primed BMDCs replicates the hightened arthritis incidence in resistant mice, highlighting the critical role of intestinal immune activation in RA. Graphical Abstract Colonization with Paleniella intestinalis bypasses genetic resistance, consistently inducing arthritis incidence in non-susceptible C57BL/6 mice P. intestinalis activates colonic CD11b + CD11c + myeloid cells, driving systemic Th17 cell differentiation In vitro, outer membrane vesicles from P. intestinalis or RA-derived S. copri RPC01 primed DCs that drive Th17 differentiation in an IL-6-dependent manner Transfer of P. intestinalis -primed DCs or its outer membrane vesicles alone increases arthritis incidence in non-susceptible C57BL/6 mice