In a review published in theRheumatology Advances in Practice journal, researchers analyzed data on the association between intestinal microbiome dysbiosis and rheumatoid arthritis (RA).

Study: The role of the microbiome in rheumatoid arthritis: a review. Image Credit: MDGRPHCS/Shutterstock.com

Background

The human microbiome comprises various bacterial, fungal, viral, and other microbes. Dysbiosis of these microbes due to diet, antibiotic use, pathology, or fecal microbiota transplantation (FMT) may alter the body’s protective immune responses.

Studies have reported a bi-directional association between the intestinal microbiota and the immunological system. The implications of elevated counts of pathogenic microbes and reduced counts of beneficial microbes have been associated with autoimmune disorders.

RA, an autoimmune disease, is characterized by immunological destruction of the self, presenting with inflammation and joint pain. Microbial alterations have been reported in RA pathogenesis; however, data on the microbe type and their specific contributions to RA development are limited.

About the review

In the present review, researchers reviewed existing data, including murine studies and human clinical trials, to explore the contribution of intestinal microbiota in RA development.

A data search was performed on January 14, 2021, using the PubMed database for English records, including their references, on the association between the intestinal microbiota and inflammatory-type joint disorders, published between 2010 and the date of the data search. The team identified 16 relevant human studies and six murine studies.

Murine studies evaluating the contribution of intestinal dysbiosis in rheumatoid arthritis

Mice colonized with a Prevotella-dominant microbiome from rheumatoid arthritis patients resulted in dendritic cell stimulation, elevated T helper 17 (Th17) production, and increased interleukin (IL)-17, 23 levels in the intestine, and rapidly induced arthritis.

Interleukin-1 receptor antagonist protein (IL-1RN) knockout (KO) mice developed autoimmune T lymphocyte-mediated arthritis, with greater Helicobacter abundance and lower Ruminococcus abundance, and elevated Th17 proportion.

Lactobacillus bifidus monocolonization resulted in rapid RA induction. Tobramycin therapy significantly improved the arthritic condition, eliminating Helicobacter species.

Inoculating segmented filamentous bacteria (SFB) reinstated Th17 proportions, inducing arthritis in mice. Significant alterations in decal microbiome diversity and composition were observed in collagen-induced arthritis (CIA) mice before visibly apparent arthritis, with intestinal inflammation and barrier impairment.

Lactobacillus administration reduced the expression of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), IL-17, and helper T-17 lymphocyte proportion and increased the expression of anti-inflammatory cytokines such as interleukin-10 and regulatory T (Treg) lymphocyte proportions, lowering RA incidence and symptom severity.

Collinsella aerofaciens increases intestinal permeability in RA murine models by lowering tight junctional protein expression, increasing the expression of inflammatory chemokines such as C-X-C motif chemokine ligand (CXCL)-1, -5, and activating the nuclear factor-kappa B (NF-κB1) pathways.

Microbiome imbalance induced Th17-dominant mucosal inflammation among genetically susceptible T lymphocytes, resulting in the activation of B lymphocytes and the production of autoantibodies that enter the circulation and migrate to the joints, contributing to RA development.

Clinical trial findings on the association between the gut microbiome and Rheumatoid Arthritis

Clinical trials were performed to assess the relationship between the intestinal microbiota and RA, using 16S ribosomal ribonucleic acid (rRNA) sequencing and shotgun metagenomic sequencing, providing complex, inconsistent, and extensive evidence.

Prevotella copri over-abundance in initial RA cases and Collinsela and Lactobacillus species proliferation in RA was reported by most studies.

Prevotella copri derived peptides bind to the human leukocyte antigen-DR isotype (HLA-DR) and induce T helper 1 (Th1)-mediated inflammation in initial RA, with immunoglobulins (Ig)-G, A targeting P. copri detected in the initial and established phases of RA.

Anti-P. copri antibody titers were associated with Th17 cytokine expression and anti-citrullinated protein antibody (ACPA) titers. P. copri DNA was detected in synovial fluid samples of RA patients. P. copriantigens structurally resemble N-acetylglucosamine-6-sulfatase-a rheumatoid arthritis-citrullinated auto-antigen, inducing B and T lymphocyte responses.

Further, studies reported a lowered abundance of butyrate-producing bacteria such as Faecalibacterium and Roseburia species in RA patients. Oral Lactobacillus administration has reduced IL-6-mediated inflammation in humans.  

The intestinal microbiota composition could be used as diagnostic and prognostic biomarkers. Alloprevotella counts positively correlate with rheumatoid factor, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) values.

IL-17A and TNF-α levels positively correlate with Gammaproteobacteria, Klebsiella, and Enterobacteriaceae counts and negatively correlate with Bifidobacterium counts. Collinsela, Akkermansia, and Euryarchaeota species abundance positively correlate with RA activity. Hemophilus counts negatively correlate with serological antibody titers.

Conclusions

Based on the review findings, the intestinal microbiome is critical for immunological activation and RA development. Gut dysbiosis precedes arthritis and local inflammation, leading to systemic inflammation among genetically predisposed individuals.

Microbiota imbalance contributes to RA pathogenesis by Lactobacillus- and Prevotella copri-mediated inflammation, Prevotella copri-mediated molecular mimicry, and Collinsella-mediated loss of intestinal barrier integrity.

However, further research, including longitudinal assessments and larger sample sizes, is required to improve understanding of the mechanisms of microbe-associated immunological responses and unravel the microbiota’s therapeutic potential for minimally invasive therapeutic interventions, comprising dietary changes and probiotic supplementations.