Molecular mechanisms and therapeutic prospects of short-chain fatty acid-mediated regulation of rheumatoid arthritis via the gut-joint axis.
Abstract
Rheumatoid arthritis (RA) is characterized by chronic synovial inflammation and progressive joint destruction, and approximately 30-40% of patients respond inadequately to currently available disease-modifying antirheumatic drugs. Growing evidence suggests that immune abnormalities driving joint inflammation may arise at mucosal sites, including the gut, lung, and periodontium, before the onset of clinical arthritis. Short-chain fatty acids (SCFAs), principally acetate, propionate, and butyrate, are major metabolites generated by anaerobic gut bacteria through dietary-fiber fermentation and participate in mucosal and systemic immunity through histone deacetylase (HDAC) inhibition, G protein-coupled receptor (GPCR) activation, and regulation of cellular metabolism. Human studies have reported reductions in SCFA-producing bacteria and lower SCFA levels in patients with RA and in some individuals at the preclinical stage; animal and in vitro studies further indicate that SCFAs can modulate the Th17/Treg balance, Breg function, macrophage polarization, osteoclast differentiation, synovial-cell activation, cartilage-matrix homeostasis, and the intestinal barrier. Microbial signals can reach the joint through routes other than soluble metabolites, including bacterial extracellular vesicles (BEVs), immune-cell migration, and neuroimmune pathways. Despite an expanding mechanistic literature, SCFA-related interventions have not produced consistent clinical effects in human RA, and translation is constrained by insufficient tissue exposure, nonselective targets, interpatient microbiota heterogeneity, and parallel pathological pathways. Starting from differences in SCFA metabolism and signaling, this review delineates the temporal positioning and transport routes of the microbiota-SCFA axis during RA development, with emphasis on immunometabolism, epigenetic regulation, bone and joint tissues, intestinal-barrier biology, and neuroimmune mechanisms. Human intervention data are then integrated to evaluate direct supplementation, targeted delivery, ecological microbiota modulation, precision stratification, and combination strategies.