Background/Purpose: Gut microbiota are strongly implicated in the pathogenesis of spondyloarthritis (SpA). Previous studies from our lab have documented extensive gut microbial dysbiosis in rats expressing HLA-B27 and human b2-microglobulin (HLA-B27 TG). The relative abundance of individual microbes is highly dependent on host genetic and environmental differences despite common immune dysregulation, indicating a complex ecological model of dysbiosis that precedes the development of arthritis. Here, we aimed to determine whether HLA-B27 TG rats that develop arthritis have a distinct gut microbial signature and host immune response.

Methods: Cohorts of mixed background (SDM) HLA-B27 TG and wild type (WT) littermates were generated by crossing HLA-B27 TG Lewis with WT Sprague-Dawley rats. SDM animals were monitored for the development of arthritis and euthanized at 4 to 6 months of age. Inflammation in the cecum and colon was assessed by histological scoring. Microbiota profiles were determined using DNA isolated from the cecum lumenal contents by 16S rRNA gene sequencing with primers specified by the Earth Microbiome Project (V4) and Illumina MiSeq. Data were quality-filtered using Quantitative Insights Into Microbial Ecology (QIIME 2). Host gene expression profiles were determined from the cecum tissue samples. RNA was isolated using a standard phenol–chloroform extraction and single-end sequencing of 50 bases was performed using an Illumina HiSeq 2000 system. Transcript expression levels (in reads per kilobase million [RPKM]) were generated and differentially expressed genes were defined for various comparisons.

Results: HLA-B27 TG SDM rats displayed early onset gut inflammation with ~30% developing arthritis by 4 months of age. No arthritis or gut inflammation was seen in WT SDM rats. Cecal and colon histology scores were similar in arthritic vs. non-arthritic HLA-B27 TG rats. There were distinct arthritis-associated microbial that were largely different from gut inflammation associated microbiota found by comparing HLA-B27 TG with WT SDM rats. Arthritic HLA-B27 SDM rats have increased abundance of phylum Bacteroides and Parabacteroides at the expense of Firmicutes. At the species level, the relative frequency of Akkermansia muciniphila and Blautia was increased, while Lachnospiraceae and [Ruminococcus] gnavus were decreased compared to non-arthritic HLA-B27 TG rats. In contrast, cecal host gene expression between HLA-B27 TG arthritic and non-arthritic rats was not significantly different.

Conclusion: We provide a preliminary identification of arthritis associated gut microbiota in HLA-B27 TG rats, which is largely distinct from gut inflammation-associated microbiota. These results may provide valuable insights into the relationship between HLA-B27, gut microbiota, and arthritis in experimental SpA although further studies to determine cause-and-effect relationships are needed.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/preliminary-identification-of-arthritis-associated-microbiota-in-experimental-spondyloarthritis/