Gut Microbiota in Rheumatoid Arthritis: Unraveling Pathogenic Mechanisms and Therapeutic Opportunities

Rheumatoid arthritis (RA), a chronic autoimmune disorder driven by genetic-environmental interplay, manifests as progressive synovitis and irreversible joint damage. Despite mechanistic advances in disease-modifying antirheumatic drugs (DMARDs) and biologics, upstream mucosal triggers of autoimmunity remain elusive. Mounting evidence implicates gut microbiota dysbiosis as a pivotal environmental factor in RA pathogenesis through multifaceted mechanisms: (1) compromising intestinal barrier integrity, (2) facilitating molecular mimicry via cross-reactive microbial antigens, (3) skewing mucosal immunity toward pro-inflammatory T helper 17 (Th17)/T follicular helper (Tfh) cell responses, and (4) generating bioactive metabolites with dual roles in regulating osteoclastogenesis and synovial inflammation. This review synthesizes recent advances in gut microbiome profiling, mechanistic studies, and preclinical models, elucidating microbial-host crosstalk in autoimmune cascades. Furthermore, we critically evaluate microbiota-directed strategies, including dietary and probiotic modulation, microbiome-informed optimization of conventional DMARDs and biologics, and investigational approaches like fecal microbiota transplantation and Chinese herbal medicine, that may offer promising adjunctive approaches to complement conventional RA management.