基于肠-脑-关节轴从微生态扰动到多靶点协同的类风湿关节炎调控策略OA

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 autoimmune responses.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 cells/Tr cells 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.Thus,a dynamic cross-system network linking the gut,brain,and joints is established,involving neural pathway coupling,immune cell migration and recruitment,endocrine regulation,and metabolic messenger-and inflammatory axis-mediated interactions.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,e.g.,tryptophan and short-chain fatty acid pathways;neuroimmune regulation attenuates inflammatory amplification via the cholinergic anti-inflammatory pathway and HPA axis modulation;and multi-target approaches integrate the advantages of microbiota,metabolism,neural,and local inflammatory control to improve therapeutic efficacy.This review elucidates RA from the integrated perspective of the gut-brain-joint axis,providing mechanistic insights into systemic inflammation and supporting the development of novel therapeutic strategies.