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

Gut Bacteria Game Changers Arthritis
Gut Bacteria: Game Changers 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 (RA).

Human microbiome project consortium studies demonstrated that healthy individuals have not only a high degree of bacterial diversity, dependent on their habitat (intestine, oral cavity, skin or vagina), but that there is also a remarkable inter-individual variability at the level of species. For example the anaerobic firmicutes/bacteroidetes spp. dominate the intestine whereas actinobacteria and proteobacteria spp. are highly abundant in the skin.

Another example – colonization of the distal small intestine by segmented filamentous bacteria (SFB) is crucial for the development of resident lamina propria dendritic cells to secrete IL-6 and IL-22 triggering the loop of Th17-T regulatory (Treg) cell generation in the new-born gut. The discovery of a link between defined members of the microbiota and the induction of Treg cells generated a huge interest. These observations indicate the importance of the bacterial community in creating a microenvironment able to sustain the generation and maintenance of the anti-inflammatory milieu.

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 rheumatoid arthritis 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

Cover Image Credit: (Left panel): Oral–gut microbiome axis. The oral microbiota can translocate to the gut in conditions of the oral–gut barrier disruption. Likewise, the gut microbes transmit to the oral cavity in both intra- and interpersonal manners, particularly related to poor hygienic conditions. This bidirectional interaction between oral and gut microbiomes develops the microbial ecosystems in both habitats through either competition or cooperation, eventually regulating the pathophysiological processes in the gastrointestinal (GI) tract. From: Oral–Gut Microbiome Axis in Gastrointestinal Disease and Cancer, Cancers 2021, 13(9), 2124;; (Right panel): In this diagram of the knee joint, the left side shows normal structures, such as smooth cartilage, thin synovium, and healthy bone. The right side shows the damaging effects of rheumatoid arthritis, such as a swollen synovium, and eroding bone and cartilage. Reproduced from Recklies AD, Poole AR, Banerjee S, et al: Pathophysiologic aspects of inflammation in diarthrodial joints, in Buckwalter JA, Einhorn TA, Simon SR (eds): Orthopaedic Basic Science: Biology and Biomechanics of the Musculoskeletal System, ed 2. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2000, pp 489-530. From: Rheumatoid Arthritis, OrthoInfo.