Dysbiotic Subgingival Microbial Communities in Periodontally Healthy Patients With Rheumatoid Arthritis

Lopez‐Oliva, Isabel; Paropkari, Akshay D.; Saraswat, Shweta; Serban, Stefan; Yonel, Zehra; Sharma, Praveen; Pablo, Paola de; Raza, Karim; Filer, Andrew; Chapple, Iain; Dietrich, Thomas; Grant, Melissa M.; Kumar, Purnima

doi:10.1002/art.40485

Cited by 78 publications

(109 citation statements)

References 26 publications

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“…Although convention still suggests otherwise, an overwhelming volume of epidemiological and experimental data indicates a microbial origin for RA (reviewed extensively by Pretorius and colleagues [11]) and therefore increasingly, a role for the altered microbiome composition in disease initiation and progression is considered. To date, RA has been associated with dysbiosis of the oral [12, 13], gastrointestinal [12, 14–22], and respiratory [23–25] microbiomes and associated with the presence of specific organisms (most commonly P. mirabilis ) within the urinary tract [26–29], suggesting that RA results in (or from) pan-microbiome dysbiosis. Studies have further begun to associate RA, or stages thereof, with the presence or absence of specific bacteria, including the expansion of rare bacterial linages [16].…”

Section: Introductionmentioning

confidence: 99%

Molecular Characterisation of the Synovial Fluid Microbiome in Rheumatoid Arthritis Patients and Healthy Control Subjects

Hammad

Liyanapathirana

Tonge

2018

Preprint

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The colonisation of specific body sites in contact with the external environment by microorganisms is both well-described and universally accepted, whereas, the existence of microbial evidence in other “classically sterile” locations including the blood, synovial space, and lungs, is a relatively new concept. Increasingly, a role for the microbiome in disease is being considered, and it is therefore necessary to increase our understanding of these. To date, little data support the existence of a “synovial fluid microbiome”.MethodsThe presence and identity of bacterial and fungal DNA in the synovial fluid of rheumatoid arthritis (RA) patients and healthy control subjects was investigated through amplification and sequencing of the bacterial 16S rRNA gene and fungal internal transcribed spacer region 2 respectively. Synovial fluid concentrations of the cytokines IL-6, IL-17A, IL22 and IL-23 were determined by ELISA.ResultsBacterial 16S rRNA genes were detected in 87.5% RA patients, and all healthy control subjects. At the phylum level, the microbiome was predominated by Proteobacteria (Control = 83.5%, RA = 79.3%) and Firmicutes (Control = 16.1%, RA = 20.3%), and to a much lesser extent, Actinobacteria (Control = 0.2%, RA = 0.3%) and Bacteroidetes (Control = 0.1%, RA = 0.1%). Fungal DNA was identified in 75% RA samples, and 88.8% healthy controls. At the phylum level, synovial fluid was predominated by members of the Basidiomycota (Control = 53.9%, RA = 46.9%) and Ascomycota (Control = 35.1%, RA = 50.8%) phyla. Statistical analysis revealed key taxa that were differentially present or abundant dependent on disease status.ConclusionsThis study reports the presence of a synovial fluid microbiome, and determines that this is modulated by disease status (RA) as are other classical microbiome niches.

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Section: Introductionmentioning

confidence: 99%

Molecular Characterisation of the Synovial Fluid Microbiome in Rheumatoid Arthritis Patients and Healthy Control Subjects

Hammad

Liyanapathirana

Tonge

2018

Preprint

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“…However, a strong evidence base exists for an immune‐mediated mechanism underlying this association. Immune deregulation in RA pathogenesis is not completely elucidated, but mounting evidence points to gut, lung and oral mucosal bacterial interfaces, where dysbiotic communities act as critical players . The most well‐studied epitope‐antibodies in RA are anti‐citrullinated protein antibodies (ACPA).…”

Section: Introductionmentioning

confidence: 99%

“…Immune deregulation in RA pathogenesis is not completely elucidated, but mounting evidence points to gut, lung and oral mucosal bacterial interfaces, where dysbiotic communities act as critical players. [4][5][6] The most well-studied epitope-antibodies in RA are anti-citrullinated protein antibodies (ACPA). The keystone periodontal pathogen P. gingivalis is the sole human pathogen known to produce a peptidylarginine deiminase (PPAD) enzyme which can citrullinate host proteins, and is believed to be an initiator of ACPA production.…”

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confidence: 99%

Biological links in periodontitis and rheumatoid arthritis: Discovery via text‐mining PubMed abstracts

Acharya

Liu

et al. 2018

J of Periodontal Research

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Background and Objective Primary research concerning molecular pathways that link rheumatoid arthritis with periodontitis is limited. Biomedical literature data mining can offer insights into putative linkage mechanisms toward hypothesis development, based on information discovery. The aim of this study was to explore potential Periodontitis‐Rheumatoid Arthritis biological links by analysing “overlapping” genes reported in biomedical abstracts. Material and Methods PubMed abstracts for terms: (a) “Periodontitis” or “Periodontal Diseases” (PD), (b) “Rheumatoid arthritis” (RA), and (c) their combination with “AND” (RA+PD), were each text‐mined to extract genes using “Human Genome Nomenclature Committee” (HGNC) symbols. A gene‐set common to RA and PD abstracts was determined (RA∩PD). Gene ontology (GO) profiles of RA∩PD and RA+PD were compared using “GoProfiler.” Minimum order protein‐protein interaction (PPI) and gene‐miRNA networks of “differential genes” between RA∩PD and RA+PD were constructed with “networkAnalyst.” Results Among 1676 genes documented in RA (10 5241 abstracts), and 893 genes in PD (80 982 abstracts), 535 genes were common (RA∩PD), from which 35 genes were also documented in RA+PD (415 abstracts). 41 GO‐terms significantly different between RA∩PD and RA+PD GO profiles represented 38 biological processes including; nitric oxide metabolism, immunoglobulin production, hormonal regulation, catabolic process down‐regulation, and leukocyte proliferation. The 500 differential genes’ PPI and gene‐miRNA networks showed REL, TRAF2, AQP1 genes, and miRNAs 335‐5p, 17‐5p, 93‐5p with genes HMOX1 and SP1 as hub nodes. Conclusions Text‐mining biomedical abstracts revealed potentially shared but un‐investigated links between PD and RA, meriting further research.

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“…Few studies have described the composition of the oral microbiota in patients with RA [10–13]. Zhang examined dental and salivary microbiome but the periodontal status of RA subjects was not defined [11].…”

Section: Introductionmentioning

confidence: 99%

“…Another study evaluated subgingival microbiota and the periodontal condition of RA subjects, but it did not evaluate the impact of RA and periodontitis independently [10]. Mikuls compared RA to Osteoarthritis patients [12] while Lopez-Oliva analyzed only RA patients without periodontitis [13]. Furthermore, neither of these studies assessed inflammatory parameters in the oral cavity.…”

Section: Introductionmentioning

confidence: 99%

Oral microbial dysbiosis linked to worsened periodontal condition in rheumatoid arthritis patients

Corrêa

Fernandes

Calderaro

et al. 2018

Preprint

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Rheumatoid arthritis (RA) is an autoimmune disorder associated with increased periodontal destruction. It is thought that RA increases the risk of periodontal disease; it is not known how it influences the oral microbiota. Our aim was to analyze the impact of RA on subgingival microbiota and its association with periodontal inflammation and RA activity. Forty-two patients with RA were compared to 47 control subjects without RA. Patients were screened for probing depth, clinical attachment level, bleeding on probing and classified as with or without periodontitis. Subgingival plaque was examined by Illumina MiSeq Sequencing of 16S rRNA gene V4 region and inflammatory cytokines were measured in saliva. RA was associated to severe periodontal disease. In addition, the severity of RA, reflected by the number of tender and swollen joints, was significantly correlated with the presence of pathogenic oral bacteria (i.e. Fusobacterium nucleatum and Treponema socransky). Non-periodontitis RA patients compared to healthy controls had increased microbial diversity and bacterial load, higher levels of pathogenic species (Prevotella, Selenomonas, Anaeroglobus geminatus, Parvimonas micra, Aggregatibacter actinomycetemcomitans) and reduction of health-related species (Streptococcus, Rothia aeria, Kingela oralis). Genes involved with bacterial virulence (i.e. lipopolysaccharide biosynthesis, peptidases) were more prevalent in the subgingival metagenome of subjects with RA. In addition, the degree of oral inflammation reflected by IL-2, IL-6, TNF-α, IFN-γ salivary levels was increased in non-periodontitis RA patients in comparison with controls. Our findings support the hypothesis that RA triggers dysbiosis of subgingival microbiota, which may contribute to worsening periodontal status.Author SummaryRheumatoid arthritis (RA) is an autoimmune disease characterized by joints inflammation, swelling, pain and stiffness. Exactly what starts this disease is still unclear. Some recent studies have suggested mucosal surfaces in the body, like those in the gums, could affect the disease process. It has been observed that people with RA have higher risk of periodontitis (a bacterial inflammatory disease of the gums), compared with the general population, and this may be the start of the autoimmune process. Also, periodontitis increases the severity of RA while interventions by treating periodontitis can improve the symptoms of RA. One of the possible mechanisms that link the higher prevalence of periodontitis in RA patients is the dysbiosis of the oral microbiota triggered by the chronic inflammation in RA. Increased levels of molecules of inflammation may affect the oral environment and change the type of bacteria that live there. Here, we examined RA patients and healthy subjects, screening their oral health and inflammatory markers. We collected their saliva and the dental plaque from the space between the teeth and the gum. We found that RA patients exhibited severe periodontitis, increased levels of inflammatory mediators on their saliva and distinct bacterial communities, with higher proportions of bacteria species linked to periodontal disease, even in patients without periodontitis. We also found that the presence of these bacteria species was linked to worse RA conditions. Our study provides new insights to understand the bi-directional mechanisms linking periodontal disease to the development of RA, showing that we need to pay attention to the oral cavity in patients with RA and refer people for dental evaluation. This practice might have a positive impact in the course of RA.

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Dysbiotic Subgingival Microbial Communities in Periodontally Healthy Patients With Rheumatoid Arthritis

Abstract: Our data demonstrate that the oral microbiome in RA is enriched for inflammophilic and citrulline-producing organisms, which may play a role in the production of autoantigenic citrullinated peptides in RA.

Cited by 78 publications

References 26 publications

Molecular Characterisation of the Synovial Fluid Microbiome in Rheumatoid Arthritis Patients and Healthy Control Subjects

Molecular Characterisation of the Synovial Fluid Microbiome in Rheumatoid Arthritis Patients and Healthy Control Subjects

Biological links in periodontitis and rheumatoid arthritis: Discovery via text‐mining PubMed abstracts

Oral microbial dysbiosis linked to worsened periodontal condition in rheumatoid arthritis patients

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