The microbiota plays a central role in human health and disease by shaping immune development, immune responses and metabolism, and by protecting from invading pathogens. Technical advances that allow comprehensive characterization of microbial communities by genetic sequencing have sparked the hunt for disease-modulating bacteria. Emerging studies in humans have linked the increased abundance of Prevotella species at mucosal sites to localized and systemic disease, including periodontitis, bacterial vaginosis, rheumatoid arthritis, metabolic disorders and low-grade systemic inflammation. Intriguingly, Prevotella abundance is reduced within the lung microbiota of patients with asthma and chronic obstructive pulmonary disease. Increased Prevotella abundance is associated with augmented T helper type 17 (Th17) -mediated mucosal inflammation, which is in line with the marked capacity of Prevotella in driving Th17 immune responses in vitro. Studies indicate that Prevotella predominantly activate Toll-like receptor 2, leading to production of Th17-polarizing cytokines by antigen-presenting cells, including interleukin-23 (IL-23) and IL-1. Furthermore, Prevotella stimulate epithelial cells to produce IL-8, IL-6 and CCL20, which can promote mucosal Th17 immune responses and neutrophil recruitment. Prevotella-mediated mucosal inflammation leads to systemic dissemination of inflammatory mediators, bacteria and bacterial products, which in turn may affect systemic disease outcomes. Studies in mice support a causal role of Prevotella as colonization experiments promote clinical and inflammatory features of human disease. When compared with strict commensal bacteria, Prevotella exhibit increased inflammatory properties, as demonstrated by augmented release of inflammatory mediators from immune cells and various stromal cells. These findings indicate that some Prevotella strains may be clinically important pathobionts that can participate in human disease by promoting chronic inflammation.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/imm.12760

The immune response to Prevotella bacteria in chronic inflammatory disease

The microbiome is represented by microorganisms which live in a symbiotic way with the mammalian. Microorganisms have the ability to influence different physiological aspects such as the immune system, metabolism and behaviour. In recent years, several studies have highlighted the role of the microbiome in the pathogenesis of autoimmune diseases. Notably, in systemic lupus erythematosus an alteration of the intestinal flora (lower Firmicutes/Bacteroidetes ratio) has been described. Conversely, changes to the gut commensal and periodontal disease have been proposed as important factors in the pathogenesis of rheumatoid arthritis. At the same time, other autoimmune diseases (i.e. systemic sclerosis, Sjogren's syndrome and anti-phospholipid syndrome) also share modifications of the microbiome in the intestinal tract and oral flora. Herein, we describe the role of the microbiome in the maintenance homeostasis of the immune system and then the alterations of the microorganisms that occur in systemic autoimmune diseases. Finally, we will consider the use of probiotics and faecal transplantation as novel therapeutic targets.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/cei.13158

The microbiome in autoimmune diseases.

A high prevalence of periodontitis has been reported in rheumatoid arthritis (RA) patients, although the strength of this association, its temporal link and the possible relationship between the severity of periodontitis and RA disease activity remain unclear. The objective of this work was to investigate whether periodontitis is associated with RA and whether periodontitis severity is linked to RA disease activity. This case–control study included 187 patients diagnosed with RA and 157 control patients without inflammatory joint disease. RA disease activity and severity were evaluated by the Disease Activity Score 28, the Simplified Disease Activity Index, the Clinical Disease Activity Index, rheumatoid factor, anti-citrullinated protein antibody titers, the erythrocyte sedimentation rate, C-reactive protein, presence of extra-articular manifestations and type of RA therapy. Exposure severity was assessed by the following periodontal parameters: plaque index, bleeding on probing, probing pocket depth and clinical attachment levels. Sociodemographic variables and comorbidities were evaluated as confounding variables. Outcome and exposure variables were compared by both parametric and nonparametric tests, and possible associations were assessed through regression analysis with a calculation for the adjusted odds ratio (OR). A significant association was demonstrated between periodontitis and RA with an adjusted OR of 20.57 (95% CI 6.02–70.27, p < 0.001). Compared with controls, all parameters related to periodontal status (plaque index, bleeding on probing, probing pocket depth and clinical attachment levels) were significantly worse in RA patients (p < 0.001). Periodontitis severity was significantly associated with RA disease activity (p < 0.001), showing in an ordinal logistic regression model an association between periodontal severity and disease activity with an adjusted OR of 2.66 (95% CI 1.24–5.74, p = 0.012). A significant association was demonstrated between periodontitis and RA, independent of other confounders. This association was more evident in patients with pronounced periodontal disease and higher RA disease activity.

/pdf/association-between-severity-of-periodontitis-and-clinical-1lbwt1zoua.pdf

Association between severity of periodontitis and clinical activity in rheumatoid arthritis patients: a case–control study

To compare the effect of non-surgical periodontal therapy on clinical and inflammatory parameters in patients with moderate to severe chronic periodontitis (CP) and rheumatoid arthritis (RA) (RA-CP) with that in CP patients without RA. Eighteen patients with RA-CP and 18 systemically healthy patients with CP were treated with scaling and root planing (SRP) within 24 h. At baseline, and at 3 and 6 months after SRP, clinical periodontal parameters, inflammatory markers, and microorganisms in subgingival biofilm were assessed. In addition, disease activity markers of RA (DAS28, CRP, ESR) and specific antibodies (RF) were monitored in the RA-CP group. In both groups, non-surgical therapy yielded to statistically significant improvements in all investigated clinical periodontal variables; in RA patients, a statistically significant decrease in serum-CRP was seen at 3 months. At all time-points, levels of inflammatory markers in GCF were higher in RA-CP than in CP patients. Counts of Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola decreased statistically significantly in CP but not in the RA-CP group. Changes of DAS28 correlated positively with those of P. gingivalis and negatively with the plaque index. Within their limits, the present data suggest that (a) non-surgical periodontal therapy improves periodontal conditions in CP patients with and without RA and (b) in patients with RA, eradication of P. gingivalis in conjunction with a high level oral hygiene may transiently decrease disease activity of RA. In patients with RA and CP, non-surgical periodontal therapy is a relevant modality not only to improve the periodontal condition but also to decrease RA activity.

Effects of non-surgical periodontal therapy on periodontal laboratory and clinical data as well as on disease activity in patients with rheumatoid arthritis

Rheumatoid arthritis and chronic periodontitis are both chronic inflammatory diseases characterized by an exacerbated inflammatory reaction that leads to destruction of bone and other connective tissue. Owing to these similarities, the relationship between these two diseases has been investigated for over two decades. In the 2013 proceedings from a workshop jointly held by the European Federation of Periodontology and American Academy of Periodontology in 2012 it was concluded that there was at least minimal evidence of an association between periodontitis and rheumatoid arthritis. In this review, we consider publications in the field over the past 5 years and determine whether the evidence for this relationship has increased.

Periodontitis and rheumatoid arthritis: An update 2012-2017.

Objective
Alterations in the microbiome, including the periodontal microbiome, may be a risk factor for rheumatoid arthritis (RA). Most studies that have analyzed this association are relatively small, focus primarily on a single periodontal pathogen (Porphyromonas gingivalis), and are not population based. This study was undertaken to investigate the association between elevated serum levels of IgG antibodies to 19 periodontal species and the prevalence of rheumatoid factor (RF) in a large nationally representative sample of adults.

Methods
The Third National Health and Nutrition Examination Survey (NHANES-III) is a cross-sectional sample of the noninstitutionalized US population (n = 33,994). Our study population included all dentate participants who were 60 years and older, did not have RA as defined by a modified version of the American College of Rheumatology 1987 criteria, and had complete data for both serum IgG antibodies against periodontal bacteria and serum RF antibody titer (n = 2,461).

Results
Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) summarizing the relationship between the 19 periodontal serum IgG antibodies and RF seropositivity ranged from 0.53 (95% CI 0.29–0.97) to 1.27 (95% CI 0.79–2.06), and 17 of the 19 observed ORs were <1.0. The ORs for RF seropositivity among participants with elevated Prevotella intermedia (0.53 [95% CI 0.29–0.97]) and Capnocytophaga ochracea (0.54 [0.31–0.95]) IgG levels were statistically significant.

Conclusion
Our findings indicate that elevated levels of IgG antibodies to periodontal bacteria are mostly unassociated with RF seropositivity in the nationally representative NHANES-III. Elevated levels of antibodies to P intermedia and C ochracea are associated with lower odds of RF seropositivity.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.39724

Jacob Kopp

Papers

Association Between Serum Antibodies to Periodontal Bacteria and Rheumatoid Factor in the Third National Health and Nutrition Examination Survey.