Microbial threads in the tapestry of rheumatoid arthritis
Jing Li, Kristine A. Kuhn
Jing Li, Kristine A. Kuhn
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Review

Microbial threads in the tapestry of rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) has a preclinical period of 5–10 years preceding the appearance of joint pain and swelling characteristic of clinical RA. Preclinical RA has been characterized by circulating IgA and IgG classes of autoantibodies targeting citrullinated protein antigens (ACPAs) that are highly specific for future clinical RA, circulating IgA plasmablasts, and autoantibody production at mucosal sites, all of which point toward mucosal tissues as the origin of immune dysregulation. In individuals at risk for developing and with established RA, oral and gut microbial shifts correlate with immune activation. Specific bacterial taxa such as Segatella copri, Subdoligranulum didolesgii, Eggerthella lenta, and Streptococcal species have been shown to contribute to the development and/or perpetuation of RA through mechanisms that include molecular mimicry, antigen citrullination, and disruption of mucosal immunity. Furthermore, microbial metabolites, including short-chain fatty acids, bile acids, and tryptophan derivatives, regulate immune homeostasis and offer potential therapeutic avenues. The gut microbiome also influences therapeutic responses by modulating conventional disease-modifying antirheumatic drugs. This Review synthesizes current knowledge on the bacterial microbiome’s role in RA pathogenesis and treatment responses, highlighting microbiome-targeted interventions as potential strategies for disease prevention and management.

Authors

Jing Li, Kristine A. Kuhn

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Figure 2

Potential mechanistic effects of the microbiome in RA pathogenesis.

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Potential mechanistic effects of the microbiome in RA pathogenesis. Bact...
Bacterial dysbiosis in the gut and oral cavity promotes barrier disruption, bacterial translocation, and altered microbial metabolite production. Increased gut permeability facilitates dissemination of microbial components such as LPS and polysaccharide A (PSA), priming innate immune responses and promoting T cell polarization toward Th1, Th17, and Tfh subsets. Microbial metabolites, including short-chain fatty acids (SCFAs), tryptophan derivatives (e.g., indole, IPA, IAA), and bile acids (e.g., LCA, DCA), modulate local and systemic immune responses. Specific bacteria contribute to RA via molecular mimicry (S. didolesgii, P. copri, E. lenta) or by promoting antigen citrullination (P. gingivalis, A. actinomycetemcomitans, S. parasanguinis), leading to the generation of autoantibodies. Neutrophil activation and NETosis further expose citrullinated microbial and host antigens. The combined effects of microbial translocation, antigenic stimulation, molecular mimicry, and citrullination establish a link between mucosal microbiota and systemic autoimmunity in RA.