Microbial Imbalance and Intestinal Permeability in the Pathogenesis of Rheumatoid Arthritis: A Mechanism Review with a Focus on Bacterial Translocation, Citrullination, and Probiotic Intervention

Abstract

This review aims to investigate the role of intestinal permeability (IP) in rheumatoid arthritis (RA), following the hypotheses that leakage of intestinal microbes can influence increased citrullination of peptides leading to anti-citrullinated protein antibody (ACPA) production and inflammation in RA; and that leaked microbes can migrate to the peripheral joints, leading to immune responses and synovitis in peripheral joints. This review explored the evidence for the link between microbial dysbiosis and increased IP in the inflammatory state in RA, as well as the role of increased citrullination and bacterial translocation in the link between microbiota and immune responses in RA. Furthermore, this research aims to evaluate the potential effect of probiotics on RA symptoms and pathogenesis via proposed mechanisms, including the support of microbial balance and suppression of inflammatory factors in RA. A systematic literature search was conducted in three tranches (review, mechanism, intervention). 71 peer-reviewed papers met the inclusions criteria and are summarized in a narrative analysis. Primary studies were critically appraised, synthesized and their relevance to clinical practice evaluated. Evidence found in this mechanism review consistently supported intestinal dysbiosis and increased IP in arthritis. An altered intestinal microbiome was demonstrated in RA with specific microbes such as Collinsella and Eggerthella correlating with increased IP, mucosal inflammation, and immune responses. Hypercitrullination and ACPA production correlated with arthritic symptoms and intestinal microbes were shown to influence hypercitrullination. Some in vitro and animal studies demonstrated a link between leakage of microbes and bacterial translocation, but further research is needed to elucidate the link between IP and citrullination. Probiotic intervention studies evidenced reductions in inflammatory markers IL-6 and TNFα, associated with proliferation of synovial tissue and pain perception in RA joint inflammation. Despite some conflict in the literature, probiotics may present a promising nutritional intervention in the suppression of both, disease activity and inflammatory markers.

Key teaching points

1. There is evidence for a dysbiotic profile of the RA gut with specific RA-associated microbes.

2. Increased intestinal permeability and leakage of PAD enzyme facilitates citrullination of peptides.

3. Hypercitrullination and ACPA production correlate to arthritic signs.

4. Microbial leakage and translocation plays a role in the pathogenesis of RA.

5. Probiotics (e.g. L. Casei 01) may reduce inflammation and ameliorate RA symptoms.

Graphical abstract

Keywords:

• Rheumatoid arthritis
• intestinal microbes
• citrullination
• intestinal permeability
• anti-citrullinated antibodies
• probiotics

Acknowledgments

This research was supported by CNELM, UK, and we are especially thankful to the expertise of Dr James Neil in the development of the methodology.

Authors’ contributions

Holly Blenkinsop: Conceptualization, investigation, visualization, writing—original draft. Karin Seidler: supervision, writing—review & editing. Michelle Barrow: review & editing.

Disclosure statement

The authors report there are no competing interests to declare.

Additional information

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.