Background/Purpose: IL-23 dependent spondylitis, arthritis and inflammatory bowel disease (IBD) recapitulate human spondyloarthropathy (SpA) in 1,3 beta glucan (curdlan)-treated SKG mice. Human SpA and SKG mice have fecal dysbiosis, with increased Bacteroidaceae and Porphyromonadaceae. In SKG mice, anti-IL-23 supports homeostatic bacteria, including Clostridiaceae, which produce the short chain fatty acid (SCFA) butyrate. Similarly, the butyrate-producing Clostridium F. prausnitzii is beneficial in IBD. To study how pathobionts and commensals impact SpA, we colonised Germ-Free (GF) SKG mice with a single pathobiont or a mix of pathobionts and commensals.

Methods: GF SKG mice were gavaged with Parabacteroides sp., Lactobacillus murinus, or altered Schaedler flora (ASF), comprising Parabacteroides, L. murinus, Mucispirullum and Clostridium spp. for 4 weeks, then given i.p. curdlan. Some groups received anti-IL-23p19 or isotype before curdlan. Parabacteroides-colonised SKG mice received sodium butyrate in the drinking water, or were gavaged with F. prausnitzii for 4 weeks. Ileal cytokines were measured by Q-PCR, bacterial translocation was analysed in ileal sections by FISH, and goblet cells were enumerated after Alcian blue staining. Ileitis and arthritis were monitored by weight loss, visual and histological scoring.

Results: SKG mice monolonised with either Parabacteroides, L. murinus, or both bacteria, but not GF mice, developed IL-23-dependent ileitis and arthritis within 5 weeks of curdlan. At week 1 post curdlan, expression of Il23a, Grp78 and sXbp1 (ER stress genes), antimicrobial peptide Reg3b and Reg3a mRNA (released by Paneth cells) was significantly increased and goblet cells decreased in the ileum of SKG mice colonised with either Parabacteroides or L. murinus, relative to GF SKG, or colonised BALB/c ileum. Concomitantly, within 1 week of curdlan, Parabacteroides or L. murinus translocated from the ileal lumen to the crypts. In contrast, SKG mice colonised with ASF, containing Clostridia, were protected from ileitis. SKG mice receiving sodium butyrate in the drinking water or gavaged with F. prausnitzii developed less weight loss and arthritis, with reduced ileal disruption.

Conclusion: Lactobacillus or Parabacteroides monocolonisation is sufficient for IL-23-dependent arthritis and ileitis progression after curdlan-mediated systemic inflammation. Pathobiont colonisation is required for curdlan to trigger ER stress, IL-23, goblet cell loss and villous permeability, permitting luminal bacterial translocation to the lamina propria. Supplementation with Clostridia or sodium butyrate reduces the ileal damage caused by pathobionts and mitigates arthritis severity.

« Back to ACR Convergence 2020

ACR Meeting Abstracts - https://acrabstracts.org/abstract/curdlan-induced-villous-permeability-luminal-pathobiont-translocation-to-the-ileal-crypts-ileitis-and-arthritis-are-mitigated-by-clostridia-in-colonised-germ-free-skg-mice/