Background/Purpose

Beta-glucan (curdlan)-treated BALB/c ZAP-70^W163C(SKG) mutant mice develop IL-23-dependent spondyloarthritis, and curdlan promotes ileitis in SKG mice housed under specific pathogen-free (SPF) but not germ-free (GF) conditions. When GF SKG mice were recolonized with altered Schaedler flora, a limited bacterial consortium known as altered Shaedler microbiota (ASM), SKG mice developed spondyloarthritis and ileitis. Relative to SPF conditions, ASM-SKG mice developed spondyloarthritis and ileitis with reduced severity, and incidence of ileitis was reduced. Relative to female mice, disease severity in male SKG mice was reduced. Our aim was to study SKG mice recolonized with ASM to understand the mechanisms by which certain gut micro-organisms drive SpA-like disease, and their relationship to gender and the curdlan inflammatory trigger. 

Methods

GF SKG mice were recolonized at the Walter and Eliza Hall Institute of Medical Research with ASM (Eubacterium plexicaudatum, Lactobacillus murinus, Mucispirillum schaedleri, 2 Clostridium sp., Lactobacillus sp., Parabacteroides sp., Firmicutes bacterium) then injected with curdlan or saline. Fecal samples were collected following recolonization and then serially after injection. The microbiota community profile was analyzed by real-time PCR. Arthritis, spondylitis and ileitis were assessed histologically in ASM-SKG mice or SPF SKG-DTR mice depleted or not of regulatory T cells (Treg).

Results

After colonization and before injection, four bacterial strains were detectable in male ASM-SKG mice (Clostridium sp, Lactobacillus murinus, Mucispirillum schaedleri, Parabacteroides sp.) with Parabacteroides the dominant species. In female ASM-SKG mice before curdlan, this same bacterial profile was observed except that the Clostridium species was not detected. After injection, the Clostridium species increased in female mice treated with curdlan but not saline-treated mice, and was maintained at similar levels in male mice. Depletion of Treg from curdlan-treated SKG mice under SPF conditions resulted in rapid and severe disease development.

Conclusion

Similar to non-obese diabetic mice, microbiota of ASM-SKG mice show a gender bias. Furthermore, these preliminary data suggest that the absence of a Clostridium species in naive female mice and outgrowth of the same species associated with curdlan-induced inflammation correlate with greater disease severity in females. Clostridium species derived from mouse and human microbiota have been shown to induce Treg in mouse colon. Together our data suggest a link between gender, microbial environment, mucosal Treg induction and propensity to disease severity, where either a lack of Clostridium species in SpA-prone mice or a lack of Treg in mice developing SpA promotes disease severity. Analysis by next generation sequencing methods will further explore gender and treatment differences in mouse gut microbiota associated with phenotype.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-gender-bias-in-gut-microbiota-of-skg-mice-colonized-with-a-limited-bacterial-consortium-associated-with-severity-of-spondyloarthritis-and-ileitis-triggered-by-beta-glucan/