Gut Microbial Functional Ecology and Microbiota-Derived Metabolites in Rheumatoid Arthritis Autoimmunity

Abstract

Highlights What are the main findings? RA-associated gut dysbiosis is characterized by stage-dependent functional ecological remodeling rather than taxonomic shifts alone. Microbiota-derived metabolites connect gut dysbiosis with epithelial barrier dysfunction, innate/adaptive immune imbalance, and joint inflammation. What are the implications of the main findings? This review places RA within a broader gut–host organ communication framework relevant to inflammatory diseases. Mechanism-informed microbiome and metabolite markers may support RA risk stratification, response prediction, and adjunctive intervention design. Abstract The gut microbiota is a key regulatory hub linking environmental exposure, the mucosal barrier, and joint inflammation, and plays an important role in the pathogenesis and progression of rheumatoid arthritis (RA). Mechanistic studies in this field mainly address two interrelated questions: how RA-associated gut microbiota modulate mucosal immunity and systemic autoimmunity through strain-level variation, niche competition, and metabolic remodeling; and how disease stage, host immune status, and drug exposure reciprocally reshape gut microbial structure and function. Accordingly, this review follows the framework of “anti-inflammatory/pro-inflammatory microbial niches—microbiota-derived metabolites—immune cell homing and migration” to summarize recent advances in the role of gut microbiota and their derivatives in RA onset, progression, and therapeutic response. Focusing on disease-stage-specific remodeling of gut functional ecology, we discuss how short-chain fatty acids, tryptophan-derived indoles, bile acids, succinate, and other microbial effector molecules regulate RA immunopathology through regulatory T cells (Treg), regulatory B cells (Breg), type 17 T helper cells (Th17), and IL-17-producing T follicular helper cells (Tfh17), dendritic cells, fibroblast-like synoviocytes, and osteoclasts. We also highlight intestinal antigen sampling, autoantibody generation, immune cell trafficking, and synovial reactivation as key links in the gut–joint axis. This review aims to shift RA microbiome research from taxonomic profiling toward stage-specific functional ecological analysis, providing a basis for risk stratification, therapeutic response prediction, and microbiota-based adjunctive interventions.