Background: The gut-joint axis exists in spondyloarthropathy, such as ankylosing spondylitis and psoriatic arthritis, where arthritis is often associated with gut dysbiosis and inflammation. Type 3 immune cytokines such as IL-17, IL-22 and IL-23 are implicated in SpA pathogenesis. Pharmaceutical agents neutralising these cytokines are in clinical use but have variable response rates in different SpA conditions. After systemic β-1,3-glucan (curdlan) injection, ZAP70 ^W163C SKG mice develop IL-23-dependent SpA-like spondylarthritis, ileitis and faecal dysbiosis with enrichment in Gram-negative pathobionts over commensals, making it a suitable model to study gut-joint axis in SpA.

Objectives: To assess the interaction of intestinal dysbiosis and spondyloarthritis, we examined IL-17A-deficient SKG mice as well as diseased SKG mice treated with anti-IL-23p19 and anti-IL-22.

Methods: Specific-pathogen-free SKG or BALB/c control mice were injected i.p. with curdlan followed by anti-IL-23p19, anti-IL-22 antibody or isotypes three weeks later. IL-17A -/- SKG mice were also injected with curdlan. At eight weeks, ileum, ankle and sacroiliac joints were collected, paraffin-embedded for histology and scored for arthritis and ileitis. Tissue sections were analysed by fluorescence imaging using universal bacterial DNA EUB338 and non-sense EUB338 control probes, combined with anti-MPO or anti-IBA-1 antibodies.

Results: At 8 weeks post-curdlan, isotype-treated SPF SKG mice developed ileitis, enthesitis, axial and peripheral arthritis while anti-IL-23p19-treated and IL-17A deficient SKG mice had much less severe disease, and BALB/c mice remained healthy. Anti-IL-22 mildly but not significantly alleviated axial and peripheral arthritis but exacerbated ileitis. IL-17 knockout significantly decreased enthesitis. In the inflamed ileum of SKG mice, EUB338+ bacteria translocated from the lumen to the gut lamina propria, colocalised with infiltrating MPO+ neutrophils and IBA-1+ resident macrophages. In arthritic axial and ankle joints, EUB338+ bacterial DNA was detected in the blood vessels, tendon entheses, ligaments and the bone marrow, associated with bone and cartilage destruction. In anti-IL-23p19-treated SKG mice, bacterial signals were detected in entheses but not the bone marrow, and they were not detected in IL-17A-deficient mice. No bacterial signal was detected in BALB/c tissues.

Conclusion: In SpA, inflammation occurs in different parts of a joint such as bone marrow and entheseal soft tissues mediated by different immune cytokines. In SKG mice, curdlan triggers permeability and ileitis that allows mucosal invasion of bacteria, and dissemination of intestinal bacterial DNA to axial and peripheral joints’ bone marrow and entheses through the vasculature. Anti-IL-23 blocks bone marrow entry of bacterial DNA but fails to limit the entheseal spread after disease onset, suggesting a potential mechanism by which inflammation is perpetuated in spondyloarthropathy.

REFERENCES: NIL.

Acknowledgements: NIL.

Disclosure of Interests: None declared.