The microbiota of the human metaorganism is not a mere bystander. These microbes have coevolved with us and are pivotal to normal development and homoeostasis. Dysbiosis of the GI microbiota is associated with many disease susceptibilities, including obesity, malignancy, liver disease and GI pathology such as IBD. It is clear that there is direct and indirect crosstalk between this microbial community and host immune response. However, the precise mechanism of this microbial influence in disease pathogenesis remains elusive and is now a major research focus. There is emerging literature on the role of the microbiota in the pathogenesis of autoimmune disease, with clear and increasing evidence that changes in the microbiota are associated with some of these diseases. Examples include type 1 diabetes, coeliac disease and rheumatoid arthritis, and these contribute significantly to global morbidity and mortality. Understanding the role of the microbiota in autoimmune diseases may offer novel insight into factors that initiate and drive disease progression, stratify patient risk for complications and ultimately deliver new therapeutic strategies. This review summarises the current status on the role of the microbiota in autoimmune diseases.

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Does the microbiota play a role in the pathogenesis of autoimmune diseases

Background: Rheumatoid arthritis (RA) and periodontitis are both chronic inflammatory disease which demonstrate similarities in terms of mechanism, histopathology and demography. An association between these conditions has been demonstrated previously but has been called into question more recently. Methods: The published databases MEDLINE, EMBASE and PsycINFO were searched using search terms related to RA and periodontitis. Articles were selected if they included data on the number of people with RA diagnosed with periodontitis (or periodontal disease parameters) compared to a control comparison group. Review articles, case reports, animal model studies, non-English language and articles with unavailable abstracts were excluded. Data was extracted, critically appraised using the Downs and Black tool and a random effect Mantel-Haenszel meta-analysis was performed. Results: 21 papers met the eligibility criteria and provided data for the meta-analysis; 17 studies (including a total of 153,492 participants) comparing RA to healthy controls and 4 (including a total of 1378 participants) comparing RA to osteoarthritis (OA). There was a significantly increased risk of periodontitis in people with RA compared to healthy controls (RR: 1.13; 95% CI: 1.04, 1.23; p=0.006; N: 153,277) with a significantly raised mean probing depth, risk of bleeding on probing (BOP) and absolute value of clinical attachment loss in those with rheumatoid arthritis. When comparing RA and OA, there was no significant difference in the prevalence of periodontitis, however the risk of BOP was greater in OA than RA. Conclusion: The significant association between RA and periodontitis is supported by the results of our systematic review and meta-analysis of studies comparing RA to healthy controls. In our meta-analysis, however, this is not replicated when comparing RA to OA controls.

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Hand to Mouth: A Systematic Review and Meta-Analysis of the Association between Rheumatoid Arthritis and Periodontitis.

Dental caries is caused by the release of organic acids from fermentative bacteria, which results in the dissolution of hydroxyapatite matrices of enamel and dentine. While low environmental pH is proposed to cause a shift in the consortium of oral bacteria, favouring the development of caries, the impact of this variable has been overlooked in microbial population studies. This study aimed to detail the zonal composition of the microbiota associated with carious dentine lesions with reference to pH. We used 454 sequencing of the 16S rRNA gene (V3–V4 region) to compare microbial communities in layers ranging in pH from 4.5–7.8 from 25 teeth with advanced dentine caries. Pyrosequencing of the amplicons yielded 449,762 sequences. Nine phyla, 97 genera and 409 species were identified from the quality-filtered, de-noised and chimera-free sequences. Among the microbiota associated with dentinal caries, the most abundant taxa included Lactobacillus sp., Prevotella sp., Atopobium sp., Olsenella sp. and Actinomyces sp. We found a disparity between microbial communities localised at acidic versus neutral pH strata. Acidic conditions were associated with low diversity microbial populations, with Lactobacillus species including L. fermentum, L. rhamnosus and L. crispatus, being prominent. In comparison, the distinctive species of a more diverse flora associated with neutral pH regions of carious lesions included Alloprevotella tanerrae, Leptothrix sp., Sphingomonas sp. and Streptococcus anginosus. While certain bacteria were affected by the pH gradient, we also found that ∼60% of the taxa associated with caries were present across the investigated pH range, representing a substantial core. We demonstrated that some bacterial species implicated in caries progression show selective clustering with respect to pH gradient, providing a basis for specific therapeutic strategies.

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Bacterial profile of dentine caries and the impact of pH on bacterial population diversity.

Integration of microbiome and epigenome to decipher the pathogenesis of autoimmune diseases.

Periodontitis (PD) and rheumatoid arthritis (RA) are immunoinflammatory diseases where leukocyte infiltration and inflammatory mediators induce alveolar bone loss, synovitis, and joint destruction, respectively. Thus, we reviewed the relationship between both diseases considering epidemiological aspects, mechanical periodontal treatment, inflammatory mediators, oral microbiota, and antibodies, using the keywords "periodontitis" and "rheumatoid arthritis" in PubMed database between January 2012 and March 2015, resulting in 162 articles. After critical reading based on titles and abstracts and following the inclusion and exclusion criteria, 26 articles were included. In the articles, women over 40 years old, smokers and nonsmokers, mainly constituted the analyzed groups. Eight studies broached the epidemiological relationship with PD and RA. Four trials demonstrated that the periodontal treatment influenced the severity of RA and periodontal clinical parameters. Nine studies were related with bacteria influence in the pathogenesis of RA and the presence of citrullinated proteins, autoantibodies, or rheumatoid factor in patients with PD and RA. Five studies investigated the presence of mediators of inflammation in PD and RA. In summary, the majority of the articles have confirmed that there is a correlation between PD and RA, since both disorders have characteristics in common and result from an imbalance in the immunoinflammatory response.

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Relationship between Periodontitis and Rheumatoid Arthritis: Review of the Literature.

Objective. Patients with RA suffer from a higher risk of periodontal attachment loss and increased oral inflammation. We hypothesize that there are pathogenetic and immunological interactions between these diseases that go beyond impaired manual dexterity accompanying advanced RA. The primary objective of the present study was to determine whether a loss of alveolar bone can be detected in RA patients during the early course of the disease. Methods. In this cross-sectional, epidemiological casecontrol study, 22 patients with early RA (ERA) were compared with 22 matched healthy controls. Oral and periodontal status, clinical activity, and sociodemographic parameters were determined. Oral microbiota were analysed using real-time quantitative PCR specific for leading oral pathogens. Results. More advanced forms of periodontitis were found in ERA patients compared with controls. ERA patients had a greater number of missing teeth [ERA 5.7 (S.D. 5.0), controls 1.9 (S.D. 1.0), P = 0.002], deeper periodontal pockets [clinical attachment level: ERA 3.4 (S.D. 0.5 mm), controls 2.7 (S.D. 0.3 mm), P < 0.000], and greater bleeding on probing [ERA 18.6% (S.D. 9.0%), controls 10.5% (S.D. 5.1%), P = 0.001] despite comparable oral hygiene. Tannerella forsythia (6.77-fold, P = 0.033) subgingivally and Streptococcus anginosus (3.56-fold, P = 0.028) supragingivally were the characteristic pathogens in ERA. Conclusion. Increased loss of periodontal attachment and alveolar bone can be detected in patients with ERA, therefore we propose that the consulting rheumatologists inform the patients that they have a higher risk of periodontal disease. It would be beneficial if these patients were referred directly for intensive dental care.

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Oral status in patients with early rheumatoid arthritis: a prospective, case–control study

Background: Certain major pathogens such as Streptococcus mutans, Lactobacillus spp. and others have been reported to be involved in caries initiation and progression. Yet, in addition to those leading pathogens, microbial communities seem to be much more diverse and individually differing. The aim of this study, therefore, was to analyze the bacterial composition of carious dentin and the plaque of caries-free patients by using a custom-made, real-time quantitative polymerase chain reaction assay (RQ-PCR). Methods: The study included 26 patients with caries and 28 caries-free controls. Decayed tooth substance and plaque samples were harvested. Bacterial DNA was extracted and tested for the presence of 43 bacterial species or species groups using RQ-PCR. Results: Relative quantification revealed that Propionibacterium acidifaciens was significantly more abundant in caries samples than were other microorganisms (fold change 169.12, p = 0.023). In the caries-free samples, typical health-associated species were significantly more prevalent. Unsupervised hierarchical cluster analysis showed a high abundance of P. acidifaciens in caries subjects and distinct but individually differing bacterial clusters in the caries-free subjects. The distribution of 11 bacteria allowed full discrimination between caries and caries-free subjects. Conclusion: Within the investigated cohort, P. acidifaciens was the only pathogen significantly more abundant in caries subjects. Cluster analysis yielded a diverse flora in caries-free subjects, whereas it was narrowed down to a small range of a few outcompeting members in caries subjects.

Bacterial biofilm composition in caries and caries-free subjects.

Objective:The composition of the oral microbiome differs distinctively between subjects with and without active caries. Still, caries research has mainly been focused on states of disease; aspects ...

https://tandfonline.com/doi/pdf/10.1080/20002297.2019.1633194

Bacterial biofilm composition in healthy subjects with and without caries experience.

Background: High-throughput technologies for typing caries or health-associated bacterial populations including PCR, DNA microarrays and next-generation sequencing techniques require significant amounts of bacterial DNA. In clinical settings, the amount of sampled DNA is often limited and amplification is therefore essential. Protocols should be able to reproducibly amplify sequences in order to maintain initial sequence ratios and should not bias the representation of particular DNA sequence types. Methods: A linear amplification protocol using DNA polymerase I was modified to permit the amplification and subsequent analysis of small amounts of bacterial DNA. The protocol was tested on human oral bacterial biofilms from different sources, including carious dentine and plaque, and compared to amplification by degenerate PCR of 16S rDNA sequences. Real-time quantitative PCR of 24 bacterial species was used as a readout system to test amplified DNA against unamplified DNA. Results: The amplification protocol reliably yielded 5–10 µg DNA from as little as 12.5 ng of template DNA. Correlation coefficients between real-time quantitative PCR results from amplified and unamplified DNA were between 0.78 and 0.98. Conclusion: The optimized protocol consistently produced amplification products from minute amounts of bacterial DNA from caries and plaque; the amplification products are suitable for downstream genetic analyses.

Amplification of minute amounts of oral bacterial DNA for real-time quantitative PCR analysis.

Background We previously showed that in this early rheumatoid arthritis (ERA) cohort with a mean disease duration of Objectives To characterize the oral microbiome associated with ERA. Methods 16S amplicon sequencing was used to analyze 88 samples of the supragingival and subgingival microbiome of 22 patients with ERA and 22 matched healthy controls. Oral and periodontal status, clinical activity of ERA and periodontitis, and socio-demographic parameters were used as explanatory variables in the next generation DNA sequencing analysis. Results Overall, a total of 4.702.161 16S RNA high-quality sequences were yielded. Using a distance-based similarity of >97% for species-level operational taxonomic unit (OTU) assignment, a total of 1054 OTUs were identified (Fig 1). The oral microbiota was equally rich and diverse in ERA and control group. Subgingivally, Prevotella oris, Prevotella oralis, Prevotella nigrescens, Alloprevotella rava and Alloprevotella tannerae were associated with early RA independent of severity of periodontitis. Conclusions Prevotella and Alloprevotella species were enriched in patients with early RA independent of severity of periodontitis. Further studies are needed to test a causal relationship of these species with onset and/or disease progression of RA. References Oral status in patients with early rheumatoid arthritis: a prospective, case-control study. Wolff B, Berger T, Frese C, Max R, Blank N, Lorenz HM, Wolff D. Rheumatology (Oxford). 2014 Mar;53(3):526–31. The lung microbiota in early rheumatoid arthritis and autoimmunity. Scher JU, Joshua V, Artacho A, Abdollahi-Roodsaz S, Ockinger J, Kullberg S, Skold M, Eklund A, Grunewald J, Clemente JC, Ubeda C, Segal LN, Catrina AI. Microbiome. 2016 Nov 17;4(1):60. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. Scher JU, Sczesnak A, Longman RS, Segata N, Ubeda C, Bielski C, Rostron T, Cerundolo V, Pamer EG, Abramson SB, Huttenhower C, Littman DR. Elife. 2013 Nov 5. Acknowledgements Wolff and Boutin contributed equally. Disclosure of Interest None declared

https://ard.bmj.com/content/annrheumdis/76/Suppl_2/754.2.full.pdf

Björn Wolff

Papers

Oral status in patients with early rheumatoid arthritis: a prospective, case–control study

Bacterial biofilm composition in caries and caries-free subjects.

Bacterial biofilm composition in healthy subjects with and without caries experience.

Amplification of minute amounts of oral bacterial DNA for real-time quantitative PCR analysis.

FRI0698 Prevotella and alloprevotella species characterize the oral microbiome of early rheumatoid arthritis