Background/Purpose:

Chronic inflammatory diseases known as spondyloarthropathies (SpA) including ankylosing spondylitis, psoriatic arthritis, reactive arthritis, and arthritis associated with inflammatory bowel disease, collectively affect 3% of the population, and are strongly heritable. Consistent with shared clinical features and genetic associations, the pathology of each disease is associated with microorganisms, and flares in bowel symptoms correlate with arthritic and spondylitic activity. However, it is not clear how the microbiome influences disease expression in SpA and how this relates to host genetic background. We sought to understand this in BALB/c wild type and ZAP-70^W163C (SKG) point-mutant mice with reduced T cell receptor signaling.

Methods:

SKG and BALB/c mice housed under specific pathogen-free (SPF) or germ-free (GF) conditions were injected intraperitoneally with microbial 1,3-D beta-glucan (curdlan). Arthritis, spondylitis and ileitis were assessed histologically. Microbiome composition in serial fecal samples of mice cohoused from weaning was analyzed by 454 pyrosequencing.

Results:

By analysis 8 weeks after curdlan, pathological severity of arthritis, spondylitis and ileitis depended on both genetic background and microbiome. Under SPF conditions, SKG mice developed severe spondylitis, arthritis and ileitis whereas curdlan-treated BALB/c developed mild arthritis and spondylitis, but no ileitis. Under GF conditions, SKG mice had reduced spondyloarthritis incidence and no ileitis. Thus development of ileitis was most sensitive to genetic background and associated microbiome i.e. absent in GF SKG mice and SPF BALB/c mice, highest incidence and severity in SPF SKG and intermediate in GF SKG mice colonized with a limited bacterial consortium. Initiation of ileal IL-23 expression, ER stress, depletion of goblet cells and IL-17 response in draining lymph nodes depended on presence of the microbiome. By pyrosequencing, microbiome content in turn depended on the genetic background of the host and the microbial response to beta-glucan over time. Consistent with transmissible suppressive microbes in BALB/c feces, ileitis but not arthritis or spondylitis severity was reduced in SKG cohoused with BALB/c mice. 

Conclusion:

Our data are consistent with impaired microbial homeostasis in SKG hosts where T cells express ZAP70^W163C, and provide a molecular basis for understanding the relationship between immune genetic susceptibility and development of SpA in response to an inflammatory environmental trigger, through host genetic effects on the gut microbiome. Modification of the microbiome presents a novel prophylatic strategy to attenuate genetic risk of SpA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/host-genetic-background-disrupts-the-relationship-between-microbiota-and-gut-mucosal-tolerance-leading-to-spondyloarthritis-and-ileitis-after-a-dectin-1-trigger/