Intervention strategies for rheumatoid arthritis based on the gut-brain-joint axis: from microecological disturbance to multi-target synergy

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation and bone destruction, accompanied by gut microbiota dysbiosis, neuroimmune dysfunction, and systemic inflammatory amplification. Increasing evidence from the gut-joint axis indicates that microbial dysbiosis disrupts intestinal barrier integrity, enhances permeability, and promotes the translocation of microbial products and antigens, thereby triggering systemic inflammation and autoimmunity. Meanwhile, alterations in microbial metabolites, including short-chain fatty acids, bile acids, and tryptophan derivatives, drive disease progression by regulating mucosal homeostasis, inflammatory resolution, and the Th17/Treg balance. Persistent dysbiosis further activates peripheral immunity and promotes the recruitment of pro-inflammatory cells and mediators to the synovium, resulting in synovial hyperplasia, cartilage degradation, and bone erosion. Concurrently, gut-derived metabolic signals, vagal afferents, and immune mediators modulate central nervous system function and neuroinflammation, whereas brain-derived stress responses regulate intestinal barrier function, microbial composition, and gut immune homeostasis via the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system, collectively exacerbating systemic inflammation and establishing a dynamic cross-system network linking the gut, brain, and joints. Microbiota-directed strategies restore microbial homeostasis and barrier integrity to reduce the initiation of inflammation; metabolic interventions rebalance immune and bone homeostasis through key signaling pathways; neuroimmune regulation attenuates inflammatory amplification via the cholinergic anti-inflammatory pathway and HPA axis modulation; and multi-target approaches integrate these mechanisms to improve therapeutic efficacy. This review elucidates RA from the integrated perspective of the gut-joint and gut-brain axes, providing mechanistic insights into systemic inflammation and supporting the development of novel therapeutic strategies.