Immunomodulatory properties of the gut microbiome: diagnostic and therapeutic potential for rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent joint inflammation, synovial hyperplasia, and progressive joint destruction. Despite advancements in biologic disease-modifying antirheumatic drugs (bDMARDs) and TNF-α blockers, many RA patients still require more effective treatment options. Although genetic and environmental factors play a role in RA development, recent studies have emphasized the influence of the gut microbiota on disease onset and progression. Dysbiosis, or an imbalance in the gut microbial composition, has been linked to immune dysregulation, increased intestinal permeability, and systemic inflammation, all contributing to RA development. Research has revealed changes in the gut microbiome of RA patients, including an increased prevalence of Prevotella copri and a decreased presence of beneficial microbes such as Bifidobacterium, Bacteroides, and Lactobacillus. RA patients exhibit altered metabolite profiles, with reduced levels of short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, which are linked to immune regulation and intestinal barrier function. Specific metabolites, such as L-arginine, phosphorylcholine, and arachidonic acid, have potential as RA biomarkers, with predictive value for diagnosis. Therapeutic approaches focusing on the microbiome, including probiotics, fecal microbiota transplantation, and traditional medicines, show promise in alleviating RA symptoms and regulating immune function. This review provides an updated overview of the immunomodulatory effects of the gut microbiome and explores its potential applications in the diagnosis and treatment of RA.

Keywords: Diagnostic markers; Immunomodulation; Microbiome; Probiotics; Rheumatoid arthritis; Therapeutics.

Fig. 1

Possible interplay between gut immunity and gut microbial dysbiosis in the development of RA. This illustration was created with https://app.biorender.com. (A) A healthy gut microbiota supports secretory IgA production, protecting the intestinal lining. Dendritic and innate lymphoid cells help naïve CD4 T cells differentiate into Th1, Treg, and Th17 cells. Treg cells release anti-inflammatory IL-10, while Th1 and Th17 produce pro-inflammatory IFN-γ and IL-17. This balance prevents local inflammation. (B) Dysbiosis promotes IgG production, triggering inflammation and epithelial damage. It downregulates IL-22 production by ILC3. Dendritic cells present citrullinated peptides to naïve CD4 T cells, favoring Th1 and Th17 over Tregs. This boosts IFN-γ and IL-17 while reducing IL-10, leading to inflammation in the lamina propria. (C) Bacterial translocation through a weakened gut barrier exposes new antigens and spreads epitopes. This triggers immune activation and systemic inflammation, contributing to the development of RA. IFN-γ interferon gamma, IgA immunoglobulin A, IgG immunoglobulin G, ILC3 innate lymphoid cell 3, IL interleukin, Treg regulatory T cell, Th1 T helper 1 cells, Th17 T helper 17 cells

Fig. 2

Immunomodulatory properties of probiotics and their role in reducing RA disease activity. This figure was produced via https://app.biorender.com. Probiotic-derived metabolites, such as SCFAs, promote the polarization of T cells toward the Th2 phenotype within the gut-associated lymphoid tissue. This Th2-mediated immune response reduces the production of pro-inflammatory cytokines, including IL-6, TNF-α, IL-1β, IL-17, and IL-23, while enhancing the secretion of anti-inflammatory cytokines like IL-10 and IL-4. Th2 cells also stimulate B cells to produce IgA, which helps prevent dysbiosis and protects the intestinal mucosal surface. Probiotics colonization supports gut barrier integrity by upregulating tight junction proteins. Together, the actions of probiotics and their metabolites contribute to reduced systemic inflammation and a subsequent decrease in RA-associated factors such as MMP-3, RANKL, MPO, PAD, CRP, and RF. CRP C-reactive protein, IgA immunoglobulin A, IL interleukins, MMP3 matrix metalloproteinase 3, MPO myeloperoxidase, PAD peptidyl arginine deiminase, RA rheumatoid arthritis, RANKL receptor activator of NF-κB ligand, RF rheumatoid factor, SCFAs short-chain fatty acids, Th2 T-helper 2 cells, TNF-α tumor necrosis factor-α, TLR toll-like receptor