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INFLAMMATION

P. gingivalis exacerbates arthritis via gut barrier dysfunction

Porphyromonas gingivalis has frequently been implicated in the pathogenesis of rheumatoid arthritis (RA), but little is known about the mechanisms linking this oral pathobiont to joint inflammation. New findings suggest that, during arthritis, disruption of intestinal resolution pathways impairs gut barrier function, which facilitates pathogenic barrier breach by P. gingivalis.

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The researchers showed that intestinal lipid mediator profiles were altered in mice with K/BxN serum transfer-induced arthritis in comparison with naive (non-arthritic) mice, with arthritic mice having reduced concentrations of several specialized proresolving mediators (SPMs), including the gut-protective n-3 docosapentaenoic acid (n-3 DPA)-derived resolvin RvD5n-3 DPA. These alterations were linked with reduced expression of genes involved in epithelial barrier function and Il10 in gut tissue, as well as a reduction in the number of mucus-producing goblet cells. Expression of IL-10 and IL-10 receptor (IL-10R) was also downregulated in lamina propria macrophages.

Further experiments revealed that inactivation of RvD5n-3 DPA during inflammatory arthritis was promoted by upregulation of the SPM-inactivating enzyme 15-prostaglandin dehydrogenase (15-PGDH) and increased metabolism of RvD5n-3 DPA to its inactive metabolite 17-oxo-RvD5n-3 DPA. Notably, incubation with immune complexes upregulated 15-PGDH expression in bone marrow–derived macrophages.

Mice with K/BxN serum transfer-induced arthritis had impaired gut barrier function in comparison with naive mice, marked by downregulation of Tjp1 and Lyz1 (encoding a tight junction molecule and an antimicrobial protein, respectively) as well as increased plasma endotoxin concentrations. Inoculation of arthritic mice with P. gingivalis exacerbated these changes and led to an increased bacterial load in the lamina propria and the colonic inner mucus layer in comparison with non-inoculated arthritic mice. This breach of bacteria across the gut barrier was not observed in non-arthritic mice inoculated with P. gingivalis.

Administration of RvD5n-3 DPA restored gut barrier function in P. gingivalis-inoculated arthritic mice; bacterial levels in mesentyric lymph nodes were reduced and the lamina propria and colonic inner mucus layer of RvD5n-3 DPA-treated mice were free of bacteria. RvD5n-3 DPA administration also restored expression of Tjp1, Lyz1 and Il10 in the intestinal epithelium. The rescue of gut barrier function following RvD5n-3 DPA administration was associated with reduced joint inflammation and swelling.

The research could have implications for the management of RA, particularly in patients with periodontal disease. “Our findings suggest that there could be scope for the stratification of patients with RA based on the presence of increased levels of P. gingivalis and/or periodontal disease, to devise personalised therapeutic strategies,” says corresponding author Magdalena Flak. “In addition, our findings suggest that new therapeutics modelled around RvD5n-3 DPA might also be useful drug candidates in RA, since they regulate both the gut barrier and joint inflammation.”

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Original article

  1. Flak, M. B. et al. Inflammatory arthritis disrupts gut resolution mechanisms, promoting barrier breakdown by Porphyromonas gingivalis. JCI Insight 4, e125191 (2019)

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Correspondence to Sarah Onuora.

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Onuora, S. P. gingivalis exacerbates arthritis via gut barrier dysfunction. Nat Rev Rheumatol 15, 512 (2019). https://doi.org/10.1038/s41584-019-0289-4

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