Background/Purpose:

Spondyloarthritis and inflammatory bowel disease (IBD) or microscopic gut inflammation co-exist in many patients. These conditions share genetic associations in the IL23R signaling pathway. Rodent models of spondyloarthritis or IBD typically improve in germ free (GF) conditions and intestinal microbial diversity is reduced in Crohn’s disease, with enrichment in Gram negative rods. Thus resident microbiota are implicated in pathogenesis. We hypothesized that microbiota directly affect incidence and severity of spondyloarthritis and ileitis in SKG mice, where the ZAP-70^W163Cmutation of the BALB/c strain reduces T cell receptor signaling.

Methods:

SKG and BALB/c mice were housed in SPF or rederived to GF conditions then injected i.p. with 1,3-D beta-glucan (curdlan). Paw width was scored for 8 weeks. Joint, tail and small intestinal histological sections were scored at sacrifice. The fecal microbiota of BALB/c and SKG mice was assessed by 454 pyrosequencing 0, 3, 7, 10 and 14 days after curdlan treatment. Double principal components analysis (DPCA) and other methods were used to compare phylogenetic groups across samples.

Results:

In SPF conditions, i.p. curdlan triggered IL-23-dependent severe spondyloarthritis and Crohn’s-like ileitis in 100% and 70% of female SKG mice respectively. BALB/c control mice developed mild peripheral arthritis without ileitis. In GF conditions, the incidence of spondyloarthritis in SKG mice was 10% and ileitis 0%. No priming of anti-proteoglycan autoantibodies occurred without spondyloarthritis. Spondyloarthritis and ileitis incidence and severity, and anti-proteoglycan antibodies were restored when GF mice were reconstituted with a limited bacterial consortium. Within days after curdlan under SPF but not GF conditions, IL-23 and Grp-78 mRNA increased in the ileum, and activated dendritic cells (DC) were recruited to the mesenteric lymph nodes, where IL-17 mRNA expression increased. By DPCA of fecal and cecal microbiota, a large shift in community structure occurred in SKG but not BALB/c mice 3 days after curdlan, related to increased Bacteroides-affiliated sequences. Segmented filamentous bacteria were absent. When BALB/c and SKG mice were cohoused after weaning and injected with curdlan at 6 weeks of age, arthritis and ileitis severity was similar in BALB/c and SKG mice cohoused in each cage.

Conclusion:

Microbiota are necessary and sufficient for priming spondyloarthritis and Crohn’s-like ileitis by DC in gut draining lymph nodes in SKG mice. The SKG mutation predisposes to lack of control of particular transmissable microbial species triggered by systemic delivery of curdlan, which enhance susceptibility to spondyloarthritis and Crohn’s-like ileitis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/incidence-and-severity-of-spondyloarthritis-and-crohns-ileitis-are-determined-by-interaction-between-the-microbiota-and-genetic-susceptibility-in-beta-glucan-treated-skg-mice/