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A8.29 Commensal intestinal microbiota drives spontaneous interleukin-1- and T helper 17-mediated arthritis in mice
  1. Shahla Abdollahi-Roodsaz1,
  2. Rebecca Rogier1,
  3. Tom Ederveen1,
  4. Harm Wopereis2,
  5. Raish Oozeer2,
  6. Marije Koenders1,
  7. Wim van den Berg1
  1. 1Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands
  2. 2Danone Research, Wageningen, The Netherlands

Abstract

Background Altered composition of intestinal microbiota in recent-onset rheumatoid arthritis (RA) and possible efficacy of oral antibiotics suggest a role of intestinal microbiota in RA. This study aimed to investigate the involvement of commensal intestinal microbiota in T cell-dependent experimental arthritis.

Methods IL-1 receptor antagonist deficient (IL-1Ra-/-) mice spontaneously developing T cell-driven IL-17-dependent autoimmune arthritis were used. Intestinal and systemic T cell differentiation and arthritis development were studied in conventional and germ-free (GF) mice. Contribution of intestinal microbiota was investigated using oral broad-spectrum and selective antibiotic treatments, combined with recolonization by specific microbiota. Multiplex 454 pyrosequencing of V5 and V6 hyper-variable regions of fecal bacterial 16S rRNA was used to identify specific microbiota associated with arthritis.

Results Compared to wild-type mice, small intestinal lamina propria of IL-1Ra-/- mice contained increased Th17 and to lower extent Th1 percentages, both of which significantly correlated with arthritis severity. Importantly, GF IL-1Ra-/- mice had a marked abrogation of arthritis along with reduced intestinal Th1 and in particular Th17. GF IL-1Ra-/- mice exhibited a notable decrease in IL-1b and IL-17 production by splenocytes upon CD3 and Toll-like receptor stimulations, suggesting abolishment of systemic Th17 response.

Relevance of intestinal microbiota was underlined by significant long-term suppression of arthritis by one-week oral treatment with Metronidazole, Neomycin and Ampicillin (each 1g/l). Interestingly, recolonization of antibiotic-treated IL-1Ra-/- mice by segmented filamentous bacteria, previously reported as a prominent intestinal Th17 inducer, was sufficient to cause full-blown arthritis. Selective elimination of Gram-negative bacteria, but not Gram-positive, suppressed arthritis, indicating members of intestinal Gram-negative commensals may drive arthritis.

High-throughput pyrosequencing revealed lower microbiota abundance (operational taxonomic units) and reduced species richness and diversity (Chao and Shannon indices, resp.) in arthritic IL-1Ra-/- compared to wild-type mice. The genus Helicobacter, belonging to Gram-negative bacteria, was found associated with arthritis severity (0.0% in wild-type versus 1.1% in arthritic mice). Validation of microbiota alterations and studies on T cell-modulatory and disease-inducing characteristics in GF mice are in progress.

Conclusion The presence of commensal intestinal microbiota is critical for the development of autoimmune T cell-driven arthritis, probably via shaping the T cell differentiation by Gram-negative bacteria. Understanding the molecular and cellular mechanisms linking the intestinal T cell response with extra-intestinal disease may help identify novel therapeutic targets in RA.

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