Treatment of ZAP-70 Mutant SKG Mice with Anti-IL-23 Antibody Alters Fecal Microbiota Composition and Prevents Outgrowth of Bacteria Associated with Susceptibility to Spondyloarthritis and Ileitis

Linda Rehaume¹, Nicholas Matigian¹, Alicia Kang¹, Olga Zbarskaya¹, Kristine Kikly², Nancy Lachner³, Joshua Daly³, Philip Hugenholtz³, Mark Morrison¹, Kim-Anh Lê Cao⁴ and Ranjeny Thomas¹, ¹Translational Research Institute, The University of Queensland Diamantina Institute, Brisbane, Australia, ²Biotechnology Discovery Research, Eli Lilly and Co, Indianapolis, IN, ³The University of Queensland, Australian Centre for Ecogenomics, Brisbane, Australia, ⁴Translational Research Instiute, The University of Queensland Diamantina Institute, Brisbane, Australia

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: IL-23, inflammatory bowel disease (IBD), microbiome, mouse model and spondylarthritis

Session Information

Date: Tuesday, November 15, 2016

Title: Spondylarthropathies Psoriatic Arthritis – Pathogenesis, Etiology - Poster II

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: Identification of disease-associated or protective bacteria may elucidate new biomarkers or probiotic supplements for people suffering from spondyloarthritis (SpA), or for people at-risk of disease development. The colitogenic Prevotella copri was associated with new-onset rheumatoid arthritis, and Prevotella spp. were increased in the cecum of HLA-B27 transgenic rats. Ankylosing spondylitis patients have increases in several bacterial families including Porphyromonadaceae. Lactobacillus murinus is protective in a murine model of colitis. Thus, microbes are associated with SpA disease progression but it is unclear how the microbial community structure differs as a result of genetic susceptibility to SpA, or the impact of additional pro-inflammatory triggers or drivers. Since IL-23 is a key driver of SpA, we hypothesized that IL-23 modifies the gut microbiota and the response to pro-inflammatory triggers of SpA.

Methods: BALB/c ZAP-70^W163C-mutant (SKG) mice housed under specific pathogen-free (SPF) conditions treated with microbial β-1,3-glucan (curdlan) develop IL-23- and microbiota-dependent SpA-like arthritis and ileitis. Altered Schaedler flora(ASF)-colonized SKG and BALB/c mice were treated one day prior to curdlan, and then weekly, with anti-IL-23 p19-specific mAb or isotype control mAb, or with curdlan or vehicle control. SPF-SKG mice were treated weekly with anti-IL-23 or isotype mAb for 3 weeks, then with curdlan or vehicle control. Fecal samples were collected longitudinally and the microbiota community profiles were analyzed by RT-PCR and next-generation sequencing. Arthritis, spondylitis and ileitis were assessed histologically.

Results: After colonization of germ-free mice with ASF, 4/8 bacterial strains were detected in ASF-SKG and ASF-BALB/c mice: Clostridium sp., Lactobacillus murinus, Mucispirillum schaedleri and Parabacteroides sp. Whilst the relative abundance of Clostridium sp. and Parabacteroides sp. was decreased in SKG, the most abundant bacterial species in both strains of mice was the Parabacteroides sp. After curdlan, the abundance of L. murinus and M. schaedleri but not Parabacteroides sp. declined in ASF-SKG mice over time, while the abundance of L. murinus and M. schaedleri did not decline in mice treated with curdlan and anti-IL-23 mAb. In SPF-SKG mice treated with anti-IL-23 mAb or anti-IL-23 mAb then curdlan, the abundance of multiple Prevotellaceae and Porphyromonadaceae spp. decreased relative to SPF-SKG mice treated with isotype then curdlan.

Conclusion: Interaction of the microbiota with the immune system of SKG mice alters the composition of both a simplified consortium and an unrestricted bacterial community. Curdlan triggers the decline of a gut-protective species within a simplified consortium. Treatment of SPF-SKG mice with anti-IL-23 mAb not only suppresses SpA development but shifts the fecal microbiota composition and prevents the usual outgrowth of bacteria associated with arthritis and inflammatory bowel disease in response to curdlan.

Disclosure: L. Rehaume, None; N. Matigian, None; A. Kang, None; O. Zbarskaya, None; K. Kikly, None; N. Lachner, None; J. Daly, None; P. Hugenholtz, None; M. Morrison, None; K. A. Lê Cao, None; R. Thomas, None.

To cite this abstract in AMA style:

Rehaume L, Matigian N, Kang A, Zbarskaya O, Kikly K, Lachner N, Daly J, Hugenholtz P, Morrison M, Lê Cao KA, Thomas R. Treatment of ZAP-70 Mutant SKG Mice with Anti-IL-23 Antibody Alters Fecal Microbiota Composition and Prevents Outgrowth of Bacteria Associated with Susceptibility to Spondyloarthritis and Ileitis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/treatment-of-zap-70-mutant-skg-mice-with-anti-il-23-antibody-alters-fecal-microbiota-composition-and-prevents-outgrowth-of-bacteria-associated-with-susceptibility-to-spondyloarthritis-and-ileitis/. Accessed .

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