Prevotella Copri and Microbiota in Rheumatoid Arthritis: Fully Convincing Evidence?

Gut microbiota regulates the host’s immune system. Microorganisms and their compounds can co-exist peacefully with the immune system and coordinate its function and regulation. Some microbial clusters may be harmful and others helpful in the respective negative or positive balance of the immune network. These insights have revealed important mechanisms for understanding and treating autoimmune and inflammatory diseases. This Editorial aims to clarify the role of specific genus of gut microbiota, such as Prevotella, in influencing the pathogenesis of Rheumatoid Arthritis (RA).

negatively influence the outcome of the disease. This compound is indeed able to stimulate abundant rate of specific immunoglobulin A (IgA) and immunoglobulin G (IgG) antibodies [14]. However, this negative effect on RA seems strain-dependent. Interestingly, the study by Marietta et al. [15], performed in an experimental model of arthritis in mice, has indeed demonstrated that a new strain of the Prevotella genus, Prevotella histicola, isolated from the colon, counteracts the insurgence of arthritis and has a positive effect on RA.
Regrettably, recent findings suggest that other species may also be involved as potential influencers in the clinical outcome of RA. The study of Chen et al. [12] correlated RA with the abundance of a gram positive called Collinsella, a genus of Actinobacteria present in the gut. Another studies conducted by Zhang et al. [16] found that the abundance of Eggerthella lenta and Collinsella correlated with RA outcomes, independently by diet or host genetic confounding factors. This suggests that RA originates at mucosal sites, which includes also the oral mucosal cavity. Porphyromonas gingivalis, a major pathogenic bacterium of periodontal diseases, is indeed recently considered to correlate with the development of RA with mechanisms similar to P. copri action in the mucosal gut [17,18].
Maeda and Takeda [19], supported by other additional authors [20], finally demonstrated that the mono-colonization of germ-free mice with P. copri was able to induce arthritis. The study was developed in a Th17 cell-dependent autoimmune arthritis, clinically resembling human RA, after injection of low doses of zymosan (a fungal component). Considering these experiments all together, it is therefore highly suggestive to think that dysbiosis dominated by P. copri in the gut contributes to RA development and its maintenance.
The study of Pianta et al. [14] had already identified a specific HLA-DR-presented peptide ((Human Leukocyte Antigen -DR isotype of T cell epitope) in a 27 kDa P. copri protein, called Pc-p27, in the synovial environment [14]. This peptide was able to increase IL-17 production as well as the IgG and IgA anti-citrullinated antibody responses, as similarly occurs in RA. The study concluded that P. copri may then contribute to the development of RA.
Thus, dysbiosis and particular bacterial clusters as P. copri first, but also Collinsella, Erghetella, the oral P. gingivalis, and others, such as the segmented filamentous bacteria (SGB) [21], or a particular strain of Lactobacillus bifidus [22] can play an important role in the pathogenesis of RA.
Further studies have evidenced that this type of dysbiosis is correlated not only to the increase of the above-mentioned microorganisms' abundance, but also to the decrease of Bacteroides, Veillonella, Eubacterium, or Haemophilus genres in the gut [9,13,16,20]. This is a clear demonstration that the unbalance of some combined and specific microbial clusters may be responsible for the pathogenesis of RA.
Thus, the presence of predisposing genetic and environmental host factors combined with a particular altered profile of the gut microbiota (also oral) may lead to an increased risk of RA.
A very recent study reveals that gut microbiome dysbiosis can be restored in a eubiotic status after administration of the so called "disease-modifying anti-rheumatic drugs" (DMART) [23]. This study indirectly confirms the important role of microbiota balance in the influence of RA disease and that some anti-rheumatic drugs can have a "probiotic" effect by inducing host microbiota modulations to generate a gut eubiosis. This and other studies have opened the way for the possibility of using real bacterial probiotics (living microorganisms that upon consumption in adequate amounts can improve the health of the intestinal microbial flora) as potential gut restoring tools to rebalance the alteration of the microbiota [24,25].
Although the studies on RA and gut microbiota need to be further corroborated by new and strong evidence, the finding that a P. copri-dominated microbiota combined with genetic and other external RA-influencing factors may represent a further risk factor for the development of the disease is highly suggestive. Thus, looking at P. copri as fecal marker along with a specific metagenomic gut dysbiotic profile in the RA patents could be a good intriguing field for better understanding the disease outcome.
More intensive human studies and in-depth in vivo experiments will surely be needed to investigate whether microbiota, or other than P. copri bacteria and specific microbial clusters can elicit severe arthritis.
In conclusion, future perspectives are mandatory to identify the precise biomolecular links between P. copri gut dysbiosis (or P. gingivalis oral dysbiosis) and the onset and maintenance of human RA. The final aim will be to develop novel therapeutic/preventive approaches as well as to study additional biological markers in RA patients by harnessing the microbiota of the body.

Conflicts of Interest:
The author declares no conflict of interest.