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IL-23 favours outgrowth of spondyloarthritis-associated pathobionts and suppresses host support for homeostatic microbiota
  1. Linda M Rehaume1,
  2. Nicholas Matigian1,2,
  3. Ahmed M Mehdi1,
  4. Nancy Lachner3,
  5. Kate L Bowerman3,
  6. Joshua Daly3,
  7. Kim-Anh Lê Cao1,4,
  8. Philip Hugenholtz3,
  9. Ranjeny Thomas1
  1. 1 Faculty of Medicine, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia
  2. 2 QFAB Bioinformatics, Institute of Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
  3. 3 Australian Centre for Ecogenomics, The University of Queensland, Brisbane, Queensland, Australia
  4. 4 Melbourne Integrative Genomics, School of Mathematics and Statistics, The University of Melbourne, Melbourne, Victoria, Australia
  1. Correspondence to Professor Ranjeny Thomas, Faculty of Medicine, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD 4102, Australia; ranjeny.thomas{at}uq.edu.au

Abstract

Objectives Certain gut bacterial families, including Bacteroidaceae, Porphyromonadaceae and Prevotellaceae, are increased in people suffering from spondyloarthropathy (SpA), a disease group associated with IL23R signalling variants. To understand the relationship between host interleukin (IL)-23 signalling and gut bacterial dysbiosis in SpA, we inhibited IL-23 in dysbiotic ZAP-70-mutant SKG mice that develop IL-23-dependent SpA-like arthritis, psoriasis-like skin inflammation and Crohn’s-like ileitis in response to microbial beta 1,3-glucan (curdlan).

Methods We treated SKG mice weekly with anti-IL-23 or isotype mAb for 3 weeks, rested them for 3 weeks, then administered curdlan or saline. We collected faecal samples longitudinally, assessed arthritis, spondylitis, psoriasis and ileitis histologically, and analysed the microbiota community profiles using next-generation sequencing. We used multivariate sparse partial least squares discriminant analysis to identify operational taxonomic unit (OTU) signatures best classifying treatment groups and linear regression to develop a predictive model of disease severity.

Results IL-23p19 inhibition in naïve SKG mice decreased Bacteroidaceae, Porphyromonadaceae and Prevotellaceae. Abundance of Clostridiaceae and Lachnospiraceae families concomitantly increased, and curdlan-mediated SpA development decreased. Abundance of Enterobacteriaceae and Porphyromonadaceae family and reduction in Lachnospiraceae Dorea genus OTUs early in disease course were associated with disease severity in affected tissues.

Conclusions Dysbiosis in SKG mice reflects human SpA and is IL-23p19 dependent. In genetically susceptible hosts, IL-23p19 favours outgrowth of SpA-associated pathobionts and reduces support for homeostatic-inducing microbiota. The relative abundance of specific pathobionts is associated with disease severity.

  • spondyloarthropathy
  • IL-23
  • microbiota
  • gastrointestinal tract
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Footnotes

  • K-ALêC, PH and RT are joint senior authors.

  • K-ALêC, PH and RT contributed equally.

  • Handling editor Josef S Smolen

  • Contributors Study concept and design: LMR, RT, KALC, PH. Acquisition and analysis and interpretation of data: all authors. Drafting of the manuscript: LMR, RT. Critical revision of the manuscript for important intellectual content: all authors. Obtained funding: RT, PH, LMR. All authors revised and approved the final manuscript to be published.

  • Funding The study was supported by NHMRC grant 1071822 and grants-in-aid from Arthritis Australia. RT was supported by Arthritis Queensland and NHMRC Research Fellowship. AMM was supported by JDRF Postdoctoral Fellowship. KALC was supported by NHMRC Career Development Fellowship and PH was supported by ARC Laureate Fellowship.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The study was approved by the University of Queensland Animal Ethics Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Raw 16s sequencing data will be provided on request to corresponding author with outline of analysis plan.

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