A Potential Central Hub of Histamine in the Microbiota–Gut–Joint Axis in Rheumatoid Arthritis: Mechanisms and Translational Implications

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by pain, persistent synovial inflammation, progressive joint destruction, and systemic immune dysregulation. Increasing evidence has revealed that the microbiota-gut-joint axis represents a crucial communication network linking intestinal dysbiosis to aberrant immune responses in RA. Among the diverse gut-derived metabolites implicated in this axis, we propose that histamine may act as a central signaling node linking microbial alterations to joint inflammation. Both host- and microbiota-derived histamine, synthesized via histidine decarboxylase (HDC), regulate immune and stromal cell activity within the joint microenvironment through histamine receptors H1R, H2R, and H4R. In addition, histamine interacts with other microbial metabolites-such as short-chain fatty acids (SCFAs) and tryptophan derivatives-forming an intricate metabolic-inflammatory network that amplifies fibroblast-like synoviocyte activation, osteoclastogenesis, and chronic inflammation. Despite accumulating evidence supporting the immunomodulatory role of histamine, the precise molecular mechanisms mediating its crosstalk with microbial and host immune pathways remain incompletely defined. This review provides a comprehensive overview of histamine-mediated regulation within the microbiota-gut-joint axis, emphasizing its interplay with other microbial metabolites and its contribution to RA pathogenesis. A deeper understanding of this histamine-centered microbiota-gut-joint axis will help elucidate its mechanistic role in immune dysregulation and may ultimately inform future strategies for restoring immune balance and preventing joint damage in RA.