Dual regulatory effects of gut microbiota and their metabolites in rheumatoid arthritis: balancing pathogenic and protective mechanisms

Abstract

Rheumatoid arthritis is a chronic autoimmune disorder characterized by destructive, symmetric joint inflammation and synovitis, resulting in substantial disability that profoundly compromises patients' quality of life. Its pathogenesis encompasses complex interactions between genetic and environmental factors. Recent advances in bacterial DNA sequencing technologies have uncovered a significant correlation between the human gut microbiota composition and rheumatoid arthritis progression. Growing clinical and experimental evidence establishes the gut-joint axis as a crucial mediator in rheumatoid arthritis pathogenesis. Comprehensive investigation of gut microbial communities and their metabolites' influence on rheumatoid arthritis mechanisms, coupled with the elucidation of microbiome's bidirectional regulatory effects in disease development, not only deepens our understanding of pathological processes but also establishes a theoretical framework for developing novel diagnostic biomarkers and personalized therapeutic interventions to enhance patient outcomes.

Keywords: bidirectional regulation; gut microbiota; gut-joint axis; intestinal metabolites; rheumatoid arthritis.

Figure 1

Schematic illustration depicting how gut microbiota and their metabolites promote the development of RA. Dysbiosis of the gut microbiome leads to an increase in harmful bacteria, which, by modulating the immune microenvironment, triggers inflammation. This microbial imbalance also enhances intestinal permeability, facilitating bacterial translocation that activates immune responses and initiates a cascade of events leading to the destruction of bone and cartilage. The immune cross-reactivity mechanism, supported by molecular simulations, elucidates how microbial antigens, due to their structural similarity to self-proteins, induce autoimmunity, subsequently causing inflammatory damage to joint tissues.

Figure 2

Schematic illustration showing how gut microbiota and their metabolites inhibit the development and progression of RA. Probiotics and their metabolites exert inhibitory effects on RA by modulating immune cell functions and regulating the expression of inflammatory cytokines. Short-chain fatty acids play a key role in this process. Additionally, various nutritional factors contribute to the repair and maintenance of the intestinal barrier by modulating microbiota composition and metabolic pathways. Dietary fiber, an essential nutrient for maintaining barrier integrity, when adequately consumed, reduces serum levels of Zonulin and calprotectin, thereby inhibiting the onset and progression of RA.

Figure 3

Schematic illustration of the translational applications of the gut microbiome in the diagnosis and treatment of RA. While RA can be managed through various methods, including oral medications, clinical outcomes exhibit significant individual variability. Interventions such as probiotic supplementation and stabilization of the intestinal barrier show potential therapeutic benefits in RA. By precisely modulating microbiota composition, interventions like probiotics, fecal microbiota transplantation, and therapies targeting the gut-joint axis may pave the way for the development of novel diagnostic biomarkers and personalized treatment strategies.