Oral Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

Curdlan-induced villous permeability is sufficient for bacterial translocation to the ileal crypts and inflamed joints, triggering ileitis and arthritis in monocolonised germ-free SKG mice (#13)

Anne-Sophie Bergot 1 , Rabina Giri 1 2 , Amy Cameron 1 , Emily Duggan 3 , Mark Morrison 1 , Jakob Begun 1 2 , Ranjeny Thomas 1
  1. UQ Diamantina Institute, Faculty of Medicine, The University of Queensland, Woolloongabba, QLD, Australia
  2. Mater Research Institute-UQ, The University of Queensland, Brisbane, QLD, Australia
  3. Gnotobiotic Facility, Translational Research Institute, Brisbane, Australia, Brisbane, QLD, Australia

Human spondyloarthropathies (SpA) are characterized by genetic predisposition, spondylitis, arthritis, and inflammatory bowel disease, with fecal dysbiosis (1). Systemic 1,3 beta glucan (curdlan)-treated, ZAP70-mutant SKG mice recapitulate human SpA, with ileitis, spondyloarthritis, and Bacteroidaceae/ Porphyromonadaceae dysbiosis, with IL-23 –dependent suppression of homeostatic Clostridiaceae (2-5). However, it is unclear whether arthritis is directly linked, or simply co-associated with, dysbiosis. In this study, we colonised Germ-Free (GF) SKG or WT ZAP70 BALB/c mice with single pathobionts Parabacteroides sp. or Lactobacillus murinus. After pathobiont-monocolonisation of SKG mice, curdlan treatment was sufficient to elicit rapid barrier dysfunction, induction of ileal Il23a, ER stress and antimicrobial peptide genes, goblet cell loss, and bacterial crypt translocation, followed by ileitis and arthritis. Barrier resilience was better without mutant ZAP70, without bacteria, with a consortium including pathobionts and Clostridium and Mucispirullum spp., or with treatment with anti-IL-23. Supplementation with oral butyrate or the butyrate-producer, F. prausnitzii, did not provide protection. We conclude that pathobiont gut barrier penetration precedes and is sufficient to drive arthritis.

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(4) Rehaume, L.M., et al., ZAP-70 genotype disrupts the relationship between microbiota and host, leading to spondyloarthritis and ileitis in SKG mice. Arthritis Rheumatol, 2014. 66(10): p. 2780-92.

(5) Benham, H., et al., Interleukin-23 mediates the intestinal response to microbial beta-1,3-glucan and the development of spondyloarthritis pathology in SKG mice. Arthritis Rheumatol, 2014. 66(7): p. 1755-67.