Background/Purpose:

In Rheumatoid Arthritis (RA), genetic predisposition and environmental risk factors promote dysbiosis of oral and fecal microbiota. We hypothesized that specific microbial taxa (operational taxonomic units, OTUs) from the oral microbiota differentiate between RA and HC and that bacteria enriched in RA subjects directly promote inflammatory arthritis.

Methods:

We chacterized a prospective cohort of RA probands, FDR and HC. Probands met ACR 2010 criteria and/or had a confirmed RA diagnosis. FDRs included parents, full siblings or offspring of an RA proband; HC were drawn from the community. From all individuals, we obtained demographics, medical history, epidemiological questionnaires and tissue collections. After DNA extraction from tongue swabs, we undertook targeted 16S rRNA gene sequencing of all samples and next-generation sequencing of 18 samples. Statistical analysis used the mixOmics R package. Axenic Streptococcus isolates (n=3 per group, 16 isolates) were produced.

Results:

116 RA patients, 63 FDR and 43 HC matched for age and gender were recruited. 56% of RA, 4% of FDR and 0% of HCs were ACPA+. Oral microbiota were altered in RA relative to HC. The oral OTU profile of some FDRs segregated with the RA patients and some segregated with HC. The oral community profile in RA was enriched in Streptococcus, Rothia, Bifidobacteria, Actinomyces and Prevotella spp. Axenic Streptococcus isolates grown from oral swabs from 16 individuals were characterised as Streptococcus Salivarius, Streptococcus Parasanguinis or Streptococcus Infantis using 16S rRNA sequencing. The abundance of Streptococcal spp. was strongly associated with smoking history. Streptococcal cell walls (SCW) were generated from reference Streptococcus pyogenes and each of the oral isolates. After one i.p. injection of purified peptidoglycan-polysaccharide polymers (PG-PS 10S) from Streptococcus pyogenes to ZAP-70^W163C-mutant BALB/c (SKG) mice, significant acute and chronic swelling occurred in wrist and ankle joints.

Conclusion:

We demonstrate distinct oral community profiles in RA patients and FDR relative to HC, which are influenced by smoking. Thus, compound genetic and environmental risks may create niches for opportunistic pathogens, such as Streptococcus, before and after the development of RA. The chronicity of SCW-induced arthritis in SKG mice suggests inability of a genetically predisposed host to effectively clear PG-PS 10S, which is resistant to degradation in vivo. Dissemination of persistently activated macrophages loaded with inflammatory bacterial remnants from the oral mucosa to lymphoid organs and peripheral joints may propagate the presentation of bacterial antigens and macrophage-driven inflammation in RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/streptococcus-species-enriched-in-the-oral-cavity-of-ra-patients-a-persistent-source-of-peptidoglycan-polysaccharide-polymers-which-drive-disseminated-synovial-inflammation/