Background/Purpose:

Identification of disease-associated or protective bacteria may elucidate new biomarkers or probiotic supplements for people suffering from 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. In ankylosing spondylitis patients, several bacterial families, including Porphyromonadaceae, were increased. Lactobacillus murinus protects against murine colitis, and ileitis does not occur in germ-free BALB/c ZAP-70^W163C-mutant (SKG) mice. Thus, microbes are associated with SpA disease progression and regulation 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. Since SpA is IL-23- and microbe-dependent in SKG mice, we examined the relationship between IL-23, gut dysbiosis and SpA development in response to microbial β-1,3-glucan (curdlan).

Methods:

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 sequencing of the 16S rRNA gene using Illumina MiSeq technology. Sequence data was analyzed using QIIME and mixOmics platforms. Arthritis, spondylitis and ileitis were assessed histologically.

Results:

After colonizing 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. The relative abundance of L. murinus increased in mice treated with curdlan and anti-IL-23 mAb compared with curdlan alone or with isotype mAb. Treatment of naïve SPF-SKG mice with anti-IL-23 mAb significantly altered the fecal microbiota composition relative to isotype mAb treatment for prolonged periods. These shifts persisted after washing out anti-IL-23. The microbiota composition of mice treated with isotype mAb and curdlan was distinct to that of mice treated with anti-IL-23 mAb with curdlan or saline, both of which clustered together regardless of curdlan or saline treatment.

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 Lactobacillus species within a simplified consortium. Moreover, IL-23 modifies the host’s support for this gut-protective species. 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. Our results suggest that positive feedback between host IL-23 and dysbiosis predisposes to a host gut environment hostile to gut-protective species and SpA development.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/il-23-promotes-fecal-microbiota-dysbiosis-associated-with-susceptibility-to-spondyloarthritis-and-ileitis-in-zap-70-mutant-skg-mice/