Microbial dysbiosis and metabolic disorders promote rheumatoid arthritis progression across successive stages

Abstract Rheumatoid arthritis (RA) is a chronic inflammatory disease that typically progresses through four stages, from mild stiffness to severe disability. The gut-joint axis is critical in RA pathogenesis, while its dynamic patterns and regulatory mechanisms throughout RA progression remain unknown. Here, we performed fecal metagenomic and serum metabolomic studies on a cohort of 122 patients from four distinct RA stages. Microbial dysbiosis and metabolomic disorders present stage-specific patterns and played crucial roles in RA pathogenesis across successive stages. In particular, Escherichi coli drove increased ascorbate degradation particularly in the second and third stages, promoting inflammation and bone destruction. Besides, abnormally high levels of serum methoxyacetic acid and cysteine-S-sulfate inhibited osteoblasts in the second stage and enhanced osteoclasts in the third stage, respectively. Furthermore, combined with analysis of 16S rRNA gene sequencing and scanning electron microscopy on joint synovial fluid from another cohort of 271 RA patients, microbial invasion of the joint was very likely to happen in the fourth stage. Our findings elucidate the role of microbial dysbiosis and metabolic disorders in successive stages of RA, which open up new avenues for RA prognosis and therapy.