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 demonstrated 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
ARTHRITIS & RHEUMATOLOGY
Frontiers in Microbiology
Updates
2023
A 2023 editorial discussed the hypothesis that rheumatoid arthritis (RA) originates from mucosal sites with a significant involvement of several bacteria. According to the author, this is supported by the presence of anti-citrullinated protein antibodies (ACPA) in the lung and interstitial inflammatory changes in at-risk for RA individuals, association of periodontitis with RA, and dysbiosis of gut microbiome in new-onset RA patients.
It appears that the factor(s) connecting the mucosal sites and joint inflammation are still elusive; yet, the author discussed the putative role of numerous bacteria, for example:
- Prevotella corpri, enriched in the gut of new-onset RA patients and in pre-clinical RA individuals;
- Porphyromonas gingivalis, as antibodies to a citrullinated gingivalis were found in ACPA-positive RA patients; Also, experimentally chronic oral infection of P. gingivalis in Lewis rats resulted in severe periodontitis and arthritis with bone erosion and ACPA production.
- A human gut bacterium, Subdoligranulum didolesgii causing arthritis in mice. The author mentioned that “didolesgi”, in fact, in native American, Cherokee Nation word means arthritis or rheumatism. Of note, didolesgii mono-colonized mice had expansion of Th17 cells and increased Th17/T regulatory (Treg) cell ratio.
According to the author, each of the bacteria associated with RA may exert its effect via different mechanisms. For example, P. gingivalis and A. actinomycetemcomitans promote protein citrullination and hypercitrullination while P. corpri and S. didolesgii may stimulate a Th17 biased response locally and systemically, but they all lead to some common inflammatory phenotypes which are called RA.
The author concluded that it might be exciting that these studies confirmed the athritogenicity of these bacteria by mono-colonization experiments in animals, but how these bacteria act in the community of microbiota in humans remains unknown.
2025 a
A 2025 review discussed the connection between gut and oral bacteria in the development of arthritis. Additionally, it explored the role of bacterial extracellular vesicles (bEVs) in inducing inflammation and their potential pathogenic roles in RA.
The review summarized recent evidence indicating that the intestines of patients in the preclinical stage of RA, an increased abundance of Prevotella species with a strong association to the disease was observed. In the oral cavity, infections by Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans can mediate the production of anti-citrullinated protein antibodies (ACPAs), potentially contributing to RA pathogenesis.
The authors discussed several pathogenic mechanisms such as:
- Metabolic dysregulation
- Molecular mimicry
- Altered intestinal permeability
- And the novel pro-inflammatory factor: bEVs
The authors discussed that Bacterial extracellular vesicles (bEVs) are spherical, double-layered vesicles secreted by bacteria, with diameters ranging from approximately 20 to 300 nm. bEVs can carry various effector molecules, including lipopolysaccharides, proteins, and nucleic acids, and participate in interactions between bacteria and host cells.
bEVs have been shown to induce a pro-inflammatory response, thereby enhancing the host defense mechanism against infections. Additionally, bEVs can influence adaptive immune responses via antigen presentation and T-cell activation. Studies indicate that bEVs are involved in the occurrence and progression of various autoimmune diseases.
The authors summarized recent evidence indicating that bacterial extracellular vesicles (bEVs) from bacteria such as F. nucleatum and P. gingivalis exert a significant pro-inflammatory effect, potentially serving as crucial pathogenic factors in the occurrence and progression of RA (Figure below).
Figure. Proposed pathogenic roles of bEVs in RA. bEVs from F. nucleatum in the intestinal tract may enhance pro-inflammatory cytokine release and macrophage polarization, potentially influencing joint inflammation via the gut-joint axis. P. gingivalis bEVs, carrying PPAD, are hypothesized to penetrate mucosal barriers, thereby promoting systemic inflammation and autoimmunity by altering immune responses and protein citrullination. These mechanisms are based on emerging evidence and require further experimental validation. From: Linking microbial communities to rheumatoid arthritis: focus on gut, oral microbiome and their extracellular vesicles, Jian Lu et al., Front Immunol. 2025 Apr 16;16:1503474. doi: 10.3389/fimmu.2025.1503474
The authors concluded that the role of bacterial factors in inflammatory diseases is being increasingly emphasized. Changes in the abundance of bacteria such as Prevotella copri in the gut, as well as infections of pathogenic bacteria like P. gingivalis and Aggregatibacter actinomycetemcomitans in the oral cavity, are considered high-risk and causative factors in the onset of RA.
Furthermore, recent studies have also highlighted the crucial role of the gut microbiota in modulating immune responses and contributing to the pathogenesis of other autoimmune diseases (ADs). For example, the authors discussed data about the gut bacterium Ruminococcus gnavus, enriched in Systemic Lupus Erythematosus (SLE). Of note, and more precisely, it has been correlated with disease activity and lupus nephritis through its ability to induce the production of anti-double-stranded DNA antibodies.
Additionally, the authors mentioned that specific gut commensals, such as segmented filamentous bacteria (SFB) and members of the Erysipelotrichaceae family, may promote autoimmune inflammation by driving the polarization of T helper 17 (TH17) cells via mechanisms involving serum amyloid A (SAA) and interleukin-23 (IL-23).
The authors also discussed new evidence suggesting a potential role of bacterial migration from the oral cavity to the gut, forming an “oral-gut axis” which could play a synergistic role in the pathogenesis of autoimmune diseases. For example, oral pathogens such as P. gingivalis can alter the gut microbiome, leading to elevated serum endotoxin levels, increased inflammatory markers, and impaired gut barrier function, ultimately exacerbating arthritis in collagen-induced arthritis (CIA) mice.
2025 b
A 2025 Research Report compared periodontal status and oral bacteria between rheumatoid arthritis (RA) patients and healthy controls (HCs). The investigators found that RA patients had more F. nucleatum subsp. animalis and V. parvula than HCs. C. gracilis was found more often in HCs than in RA patients.
The authors discussed that their findings suggest that F. nucleatum subsp. animalis and V. parvula may be related to the development and aggravation of RA. According to the authors they did not find a direct association between P. gingivalis and RA, but P. gingivalis may aggravate periodontitis and tissue inflammation, which may affect RA.
Cover Image Credit: (Left panel): 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.
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