Rheumatoid Arthritis Initiation and Mucosal Immunity: Mechanisms Digestion

Rheumatoid arthritis (RA) is increasingly recognized as a mucosa-initiated autoimmune disease rather than a disorder that begins within the joint itself. This review synthesizes epidemiological, mechanistic, and experimental evidence supporting a model in which mucosal dysbiosis, altered microbial metabolites, barrier dysfunction, and antigenic mimicry converge to prime systemic autoimmunity. Across gut, oral, and pulmonary sites, RA and at-risk individuals exhibit reproducible microbial shifts, reduced short-chain fatty acid production, increased succinate and indole signaling, and elevated permeability. These changes skew dendritic cell activation, amplify IL-1β/IL-6/IL-23–dependent Th17 responses, impair Treg stability, and lower systemic immune tolerance thresholds. In parallel, microbial citrullinated epitopes and cross-reactive peptides—particularly from Prevotella and Streptococcus species—provide antigenic substrates that may drive ACPA maturation and epitope spreading. While direct causality remains unresolved, we propose that RA initiation reflects cumulative immune conditioning at mucosal interfaces, with joint inflammation emerging as a secondary, tissue-focused consequence of a systemically primed inflammatory state.