Gut commensal Parabacteroides distasonis alleviates inflammatory arthritis

Abstract

Objective: Gut microbiota dysbiosis is closely linked to the pathogenesis of rheumatoid arthritis (RA). We aimed to identify potential probiotic gut microbes that can ameliorate the development of RA.

Design: Microbiota profiling in patients with RA and healthy individuals was investigated via 16S rDNA bacterial gene sequencing and shotgun metagenomics. Collagen-induced arthritic mice and TNF-α transgenic mice were used to evaluate the roles of the gut commensal Parabacteroides distasonis in RA. The effects of P. distasonis-derived microbial metabolites on the differentiation of CD4⁺ T cells and macrophage polarisation were also investigated.

Results: The relative abundance of P. distasonis in new-onset patients with RA and patients with RA with history of the disease was downregulated and this decrease was negatively correlated with Disease Activity Score-28 (DAS28). Oral treatment of arthritic mice with live P. distasonis (LPD) considerably ameliorated RA pathogenesis. LPD-derived lithocholic acid (LCA), deoxycholic acid (DCA), isolithocholic acid (isoLCA) and 3-oxolithocholic acid (3-oxoLCA) had similar and synergistic effects on the treatment of RA. In addition to directly inhibiting the differentiation of Th17 cells, 3-oxoLCA and isoLCA were identified as TGR5 agonists that promoted the M2 polarisation of macrophages. A specific synthetic inhibitor of bile salt hydrolase attenuated the antiarthritic effects of LPD by reducing the production of these four bile acids. The natural product ginsenoside Rg2 exhibited its anti-RA effects by promoting the growth of P. distasonis.

Conclusions: P. distasonis and ginsenoside Rg2 might represent probiotic and prebiotic agents in the treatment of RA.

Keywords: Intestinal microbiology; arthritis; bile acid metabolism; inflammation.