Gut and Gingival Bacteria: Game Changers or Innocent Bystanders in Rheumatoid Arthritis?

Gut Bacteria Rheumatoid Arthritis

Several publications in the last 2-3 years brought more interest in the link between gut and gingival bacteria or microbiota, and human health and diseases, and particularly their possible game changer role in the pathogenesis of rheumatoid arthritis.

The human gastrointestinal tract comprises approximately 1014 bacterial microbes and amounts to a biomass of approximately 2 kg, and according to some estimates this corresponds to a ratio for microbial to human cells approximately 1.3:1 (cf. JD Forbes, G Van Domselaar & CN Bernstein, Front Microbiol. 2016; 7: 1081).

There is now an increasing body of evidence suggesting that alterations of gut flora are common in some immune-mediated inflammatory diseases such as inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis (RA).

Gut bacteria as a pathogenic factor in RA was perhaps first recognized in 1965 by Mansson and Colldahl reporting increased amounts of Clostridium perfringens type A in the intestinal flora of RA patients. This later became clear to be a non-specific findings, as being recorded in other chronic arthritides.

Recent research using germ-free and gnotobiotic experimental animal models indicates that a dysbiosis of the gut microbiota is associated with the pathogenesis of inflammatory arthritis. For example, in IL-1 receptor antagonist-knockout (Il1rn-/-) mice, applying gnotobiological methods, the introduction of the commensal species Lactobacillus bifidus resulted in disease onset.

In humans, recent studies in RA patients indicate that they harbor significantly less bifidobacteria, but significantly more Lactobacillus when compared to healthy controls. Compared to patients with chronic RA and healthy controls, the cohort of patients with new-onset RA has a significantly higher abundance of Prevotella copri. Importantly, Prevotella is typically low in healthy individuals.

Of note, healthy individuals have a high degree of bacterial diversity, dependent on their habitat (intestine, oral cavity, skin or vagina), and also a remarkable inter-individual variability. In contrast, a 2016 Genome Medicine study demonstrates that RA patients have decreased gut microbial diversity, which correlates with disease duration and autoantibody levels.

However, all these findings remain mostly correlative and do not necessarily represent causation.

Recent evidence also suggests a pathogenic role for the altered oral microbiota in RA. A 2015 Nature Medicine study reports alterations in the gut, dental or saliva microbiome in RA patients from healthy controls. Thus, Haemophilus spp. were depleted, but Lactobacillus salivarius was over-represented in patients with RA.

Periodontitis (PD)-associated bacteria, e.g., Porphyromonas gingivalis are often linked to chronic inflammatory oral disease, and, interestingly, RA and the severe forms of PD share several features, such as increased levels of pro-inflammatory cytokines and metalloproteinases. In fact, Porphyromonas gingivalis was suggested to provide a trigger for the development of RA, also being the only known bacterium carrying a peptidyl-arginine-deiminases (PAD) enzyme.

Of note, the first case of a complete recovery after periodontal treatment, in a patient with newly onset of RA has been recently reported, suggesting that prompt periodontal infection treatment may eventually induce disease regression.

According to Jose U. Scher et al. the microbiome may contribute causally to RA through 3 major mechanisms. This includes the ‘state of dysbiosis’, a possible ‘provision of neoantigens’ (i.e., P. gingivalis–driven citrullination of peptides and generation of ACPAs – the anti–citrullinated protein antibodies), and/or the ‘generation of costimulatory signals’. In this one, e.g., in the presence of potentially arthritogenic ACPAs, the disease is triggered only through a “second event,” driven by bacterial components and consequent cellular immune response.

Read more: Journal of Translational Medicine
Frontiers in Microbiology
Blog Arthritis Foundation