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Streptococcus species enriched in the oral cavity of patients with RA are a source of peptidoglycan-polysaccharide polymers that can induce arthritis in mice

Abstract

Objectives Analysis of oral dysbiosis in individuals sharing genetic and environmental risk factors with rheumatoid arthritis (RA) patients may illuminate how microbiota contribute to disease susceptibility. We studied the oral microbiota in a prospective cohort of patients with RA, first-degree relatives (FDR) and healthy controls (HC), then genomically and functionally characterised streptococcal species from each group to understand their potential contribution to RA development.

Methods After DNA extraction from tongue swabs, targeted 16S rRNA gene sequencing and statistical analysis, we defined a microbial dysbiosis score based on an operational taxonomic unit signature of disease. After selective culture from swabs, we identified streptococci by sequencing. We examined the ability of streptococcal cell walls (SCW) from isolates to induce cytokines from splenocytes and arthritis in ZAP-70-mutant SKG mice.

Results RA and FDR were more likely to have periodontitis symptoms. An oral microbial dysbiosis score discriminated RA and HC subjects and predicted similarity of FDR to RA. Streptococcaceae were major contributors to the score. We identified 10 out of 15 streptococcal isolates as S. parasalivarius sp. nov., a distinct sister species to S. salivarius. Tumour necrosis factor and interleukin 6 production in vitro differed in response to individual S. parasalivarius isolates, suggesting strain specific effects on innate immunity. Cytokine secretion was associated with the presence of proteins potentially involved in S. parasalivarius SCW synthesis. Systemic administration of SCW from RA and HC-associated S. parasalivarius strains induced similar chronic arthritis.

Conclusions Dysbiosis-associated periodontal inflammation and barrier dysfunction may permit arthritogenic insoluble pro-inflammatory pathogen-associated molecules, like SCW, to reach synovial tissue.

  • rheumatoid arthritis
  • first-degree relatives
  • oral
  • microbiome
  • streptococci
  • cell walls

Data availability statement

Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as supplementary information. Assembled genomes and raw 16S rRNA gene amplicon sequencing data are available via NCBI BioProject PRJNA656387. Prokka annotated genomes available at https://github.com/katebowerman/Streptococcus. Other data are available on request to corresponding author.

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