Gut Microbiota Modulation: A Novel Strategy for Rheumatoid Arthritis Therapy

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease that leads to joint inflammation, progressive tissue damage and significant disability, severely impacting patients' quality of life. While the exact mechanisms underlying RA remain elusive, growing evidence suggests a strong link between intestinal microbiota dysbiosis and the disease's development and progression. Differences in microbial composition between healthy individuals and RA patients point to the role of gut microbiota in modulating immune responses and promoting inflammation. Therapies targeting microbiota restoration have demonstrated promise in improving treatment efficacy, enhancing patient outcomes and slowing disease progression. However, the complex interplay between gut microbiota and autoimmune pathways in RA requires further investigation to establish causative relationships and mechanisms. Here, we review the current understanding of the gut microbiota's role in RA pathogenesis and its potential as a therapeutic target.

Keywords: bacterial metabolites; bacterial translocation; dysbiosis; gut microbiota; molecular mimicry; rheumatoid arthritis.

Figure 1

Mechanisms linking oral and gut microbiota dysbiosis to RA pathogenesis. The figure illustrates the contrasting states of a healthy individual and a patient with rheumatoid arthritis (RA). Healthy state (left panel): A balanced gut microbiota ensures a robust intestinal barrier regulated by tight junction molecules like ZO-1. Beneficial microbes such as Faecalibacterium prausnitzii and Bacteroides fragilis produce short-chain fatty acids (SCFAs) and polysaccharide A, which support immune tolerance by promoting Treg differentiation, balancing Th1/Th17 responses, and producing anti-inflammatory cytokines (e.g., IL-10). RA state (right panel): Dysbiosis leads to increased intestinal permeability via zonulin release and compromised tight junctions, facilitating bacterial translocation. Pathogenic microbes, including Prevotella copri and Fusobacterium nucleatum, interact with immune cells (B cells, T cells and dendritic cells) to induce inflammatory responses, producing autoantibodies (ACPA and RF) and inflammatory cytokines (IL-6, IL-1 and TNF-α). Molecular mimicry by bacterial proteins further exacerbates autoimmunity. Oral pathogens like Porphyromonas gingivalis contribute to ACPA formation via PAD enzymes and heightened pro-inflammatory cytokines through lipopolysaccharides (LPSs). Virulence factors such as FadA from F. nucleatum drive joint inflammation through outer membrane vesicles (OMVs).

Figure 2

Gut microbiota-targeted strategies for RA therapy. This figure illustrates approaches to modulate gut microbiota and alleviate RA symptoms: (1) probiotics and prebiotics (Lactobacillus, Bifidobacterium, etc.) to restore microbial balance; (2) diet and lifestyle rich in fibre, polyphenols, vitamins and SCFAs, alongside smoking cessation and reduced intake of harmful foods; (3) traditional Chinese medicine (TCM) (e.g., Atractylodes koreana and berberine) to balance microbiota and reduce inflammation; and (4) faecal microbiota transplantation (FMT) to restore microbial diversity and immune homeostasis. These interventions collectively target dysbiosis and systemic inflammation in RA.