Dysbiosis in the oral microbiomes of anti-CCP positive individuals at risk of developing rheumatoid arthritis

Abstract

ObjectivesAn increased prevalence of periodontitis and perturbation of the oral microbiome has been identified in patients with rheumatoid arthritis (RA). The periodontal pathogen Porphyromonas gingivalis may cause local citrullination of proteins, potentially triggering anti-citrullinated protein antibody production. However, it is not known if oral dysbiosis precedes the onset of clinical arthritis. This study comprehensively characterised the oral microbiome in anti-cyclic citrullinated peptide (anti-CCP) positive at-risk individuals without clinical synovitis (CCP+at risk).MethodsSubgingival plaque was collected from periodontally healthy and diseased sites in 48 CCP+at risk, 26 early RA and 32 asymptomatic healthy control (HC) individuals. DNA libraries were sequenced on the Illumina HiSeq 3000 platform. Taxonomic profile and functional capability of the subgingival microbiome were compared between groups.ResultsAt periodontally healthy sites, CCP+at risk individuals had significantly lower microbial richness compared with HC and early RA groups (p=0.004 and 0.021). Microbial community alterations were found at phylum, genus and species levels. A large proportion of the community differed significantly in membership (523 species; 35.6%) and structure (575 species; 39.1%) comparing CCP+at risk and HC groups. Certain core species, including P. gingivalis, had higher relative abundance in the CCP+at risk group. Seventeen clusters of orthologous gene functional units were significantly over-represented in the CCP+at risk group compared with HC (adjusted p value <0.05).ConclusionAnti-CCP positive at-risk individuals have dysbiotic subgingival microbiomes and increased abundance of P. gingivalis compared with controls. This supports the hypothesis that the oral microbiome and specifically P. gingivalis are important in RA initiation.

Oral Microbiota Identifies Patients in Early Onset Rheumatoid Arthritis

“…In general, enrichments of periodontitis-associated species, such as in Prevotella , Alloprevotella , Fusobacterium and Filifactor were reported in patients with established RA [ 19 , 43 , 44 ]. A few studies, mainly recent ones, have targeted early-stage RA and patients with ACPA positive arthralgia but no sign of arthritis, i.e., patients at risk for RA [ 6 , 9 , 18 , 21 ]. Some report that periodontal signs are more severe already at early RA/at-risk-stages [ 6 , 18 ], but this was not confirmed in recent Dutch [ 21 ] or, though there was a tendency, in the present Swedish population.…”

“…However, the role of P. gingivalis and Aa remains unclear in RA development. Thus, some studies using 16S ribosomal RNA (16S rRNA) high-throughput sequencing find a higher abundance of P. gingivalis and/or Aa in early and established RA as well as in patients at risk for RA (ACPA positive arthralgia) [ 6 , 9 , 18 ], whereas others do not [ 19 , 20 , 21 , 22 ]. Anyhow, several of the studies emphasize the importance of characterizing the entire microbiota, map to the species level, and distinguishing between periodontally healthy and diseased states and treatment immune modifying anti-rheumatic drugs.…”

Therapeutic Effect of Matrine on Collagen-Induced Arthritis Rats and Its Regulatory Effect on RANKL and OPG Expression

“…Besides genetic factors, P. gingivalis represents one of the main environmental factors that can lead to autoimmune arthritis, which can induce citrullinated peptides. Citrullinated peptides are a source of anticitrullinated antibodies (ACPAs), which can predict the occurrence and the future development of RA [ 14 ]. An increasing number of studies have found a correlation between P. gingivalis infection and ACPA-positive RA [ 15 ].…”

Risk Factors for Developing Rheumatoid Arthritis in Patients With Undifferentiated Arthritis and Inflammatory Arthralgia

“…Mikuls et al described that anti-P. gingivalis concentrations have been significantly associated with autoantibody-positive and high-risk status of developing RA (130). There is a characteristic alteration in the composition of salivary microbes in individuals at high-risk for RA, suggesting that oral microbiota dysbiosis occurs in the "pre-clinical" stage of RA (131)(132)(133). Moreover, among patients with RA, PD severity appears to independently predict RA severity (134,135).…”