The gut homeostasis-immune system axis: novel insights into rheumatoid arthritis pathogenesis and treatment

Abstract

Rheumatoid arthritis is a widely prevalent autoimmune bone disease that imposes a significant burden on global healthcare systems due to its increasing incidence. In recent years, attention has focused on the interaction between gut homeostasis and the immune system, particularly in relation to bone health. Dysbiosis, which refers to an imbalance in the composition and function of the gut microbiota, has been shown to drive immune dysregulation through mechanisms such as the release of pro-inflammatory metabolites, increased gut permeability, and impaired regulatory T cell function. These factors collectively contribute to immune system imbalance, promoting the onset and progression of Rheumatoid arthritis. Dysbiosis induces both local and systemic inflammatory responses, activating key pro-inflammatory cytokines such as tumor necrosis factor-alpha, Interleukin-6, and Interleukin-17, which exacerbate joint inflammation and damage. Investigating the complex interactions between gut homeostasis and immune regulation in the context of Rheumatoid arthritis pathogenesis holds promise for identifying new therapeutic targets, revealing novel mechanisms of disease progression, and offering innovative strategies for clinical treatment.

Keywords: gut homeostasis; immune system; novel therapeutic approaches; pathogenesis; rheumatoid arthritis.

Figure 1

The intestinal mucosal immune network represents a intricate system comprising innate, adaptive, and immunoglobulin A-mediated immune mechanisms. Epithelial cells and dendritic cells recognize antigens via pattern recognition receptors and present them to T and B lymphocytes within lymphoid tissues, triggering adaptive immune responses. Simultaneously, they activate signaling cascades, stimulate the production of cytokines and antimicrobial peptides, and mount acute inflammatory reactions to eliminate offending agents. B cells differentiate into plasma cells that secrete immunoglobulin A, which is then transported into the gut lumen, where it neutralizes antigens and pathogens through its binding capabilities.

Figure 2

Schematic representation of intestinal homeostasis influencing rheumatoid arthritis pathogenesis. (A) Dysbiosis of the gut microbiome can trigger an immune response. (B) Damage to the gut barrier can trigger inflammation. (C) Immune cells residing in the gut play a regulatory role in modulating inflammatory cytokine production. Gut microbial imbalance is associated with aberrant inflammatory cytokine profiles and dysregulated immune responses, which collectively contribute to the development and progression of rheumatoid arthritis.

Figure 3

Schematic representation of the mechanisms by which intestinal homeostasis regulates rheumatoid arthritis pathogenesis. (A) Disruption of the intestinal barrier leads to increased intestinal permeability, induces T cell-mediated inflammatory responses, and facilitates the migration of autoreactive T cells from the gut to the joints, triggering rheumatoid arthritis in the articular tissues. (B) Metabolites derived from the intestinal microbiota can promote systemic inflammation; lipopolysaccharides from intestinal bacteria translocate into the circulation, are recognized by Toll-like receptors, and stimulate the Nuclear Factor kappa-light-chain-enhancer of activated B cells signaling pathway, thereby exacerbating inflammatory processes and contributing to rheumatoid arthritis development. (C) Dysbiosis of the intestinal microbiome can perturb the host immune system and its functions, interfere with T cell differentiation, and dysregulate host immune responses. (D) Rheumatoid arthritis arises from the convergence of multiple inflammatory pathways, ultimately leading to an imbalanced immune system and perpetuating the chronic inflammatory state.