The Oral-Gut-Immune-Nutrition Axis in Rheumatoid Arthritis: Molecular Mechanisms and Therapeutic Implications

Abstract

Rheumatoid arthritis is a chronic systemic autoimmune disease that arises from complex interactions among genetic susceptibility, environmental factors, and immune dysregulation. Growing evidence indicates that microorganisms residing in the oral cavity and gastrointestinal tract, together with dietary factors, play a central role in shaping inflammatory and autoimmune responses in rheumatoid arthritis, forming an interconnected microbiome-immune-nutrition axis. Alterations in the composition and function of oral and intestinal microbial communities are associated with disruption of mucosal barrier integrity, activation of innate and adaptive immune pathways, increased differentiation of proinflammatory T lymphocyte subsets, and loss of immune tolerance that promotes autoantibody production. In addition, microbially derived metabolites, particularly short-chain fatty acids, provide a mechanistic link between microbial ecology, immune regulation, and bone metabolism. Diet represents a key upstream modulator of this axis. Dietary patterns rich in anti-inflammatory nutrients support microbial diversity and immunoregulatory metabolite production, whereas diets high in processed foods and saturated fats favor proinflammatory microbial profiles. Accumulating clinical evidence suggests that nutritional strategies and microbiome-targeted dietary interventions may reduce systemic inflammation and disease-related comorbidities when used alongside standard pharmacological treatments. Taken together, the microbiome-immune-nutrition axis represents a modifiable and clinically meaningful target in rheumatoid arthritis, emphasizing the need for interdisciplinary research and well-designed clinical trials to translate these insights into personalized approaches for disease management. The aim of this review is to integrate current mechanistic and clinical evidence on the interactions between the microbiome, immune system, and nutrition in rheumatoid arthritis, with a focus on their pathogenic relevance, therapeutic potential, and implications for personalized, diet-based interventions.

Keywords: dietary modulation; gut–joint axis; immune dysregulation; mucosal immunity; oral microbiome; rheumatoid arthritis; short-chain fatty acids.

Figure 1

The oral–gut–immune–nutrition axis in RA pathogenesis. Oral dysbiosis (periodontitis) initiates autoantibody formation via P. gingivalis-mediated citrullination. This dysbiosis extends to the gut, where microbial imbalances and short-chain fatty acid deficiency compromise barrier integrity, sustaining systemic inflammation and joint damage. Diet acts as a crucial environmental modulator of this entire axis. Abbreviations: ↑, activation/increase; ↓, inhibition/reduction; PAD, peptidylarginine deiminase; LtxA, leukotoxin A; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3; SCFAs, short-chain fatty acids; Th17, T helper 17 cells; Treg, regulatory T cells; IL, interleukin; TNF, tumor necrosis factor; RA, rheumatoid arthritis. Created in https://BioRender.com (accessed on 10 January 2026).