Background/Purpose: HLA-B27 has been hypothesized to alter gut microbiota and host-microbe interactions to promote spondyloarthritis (SpA). In HLA-B27 transgenic (HLA-B27 Tg) rats with experimental SpA, we have reported that HLA-B27 effects on gut microbiota diverge on different genetic backgrounds despite common patterns of immune dysregulation. Using an integrative analysis of gut microbiome and host transcriptome (inter-omics), we asked which microbes correlate with immune dysregulation on different genetic backgrounds, and whether they have similar functional implications.

Methods: We correlated the relative frequency of gut microbes determined by 16S rRNA gene sequencing, with host gene expression determined by RNAseq, for cecum and colon samples derived from 193 HLA-B27 Tg and wild type (WT) rats from Dark Agouti (DA), Lewis (LEW) and Fischer (F344) backgrounds. Microbes with a relative abundance of >0.1% in at least one sample, and genes with expression values (reads per kilobase million; RPKM) >1 in at least one sample and a coefficient of variation >0.8 across the dataset were included. Significant correlation coefficients (r) between the microbial relative frequency and transcript RPKM value (p<0.05) were used to identify relevant relationships. PICRUSt was used to predict microbial functions based on metagenomic profiles, which were then correlated with disease severity (histology scores), and significant metabolic pertubations associated with inflammation were identified (q<0.05 based on FDR-corrected p-values was used).

Results: Inter-omic analysis revealed several microbes associated with dysregulated cytokines driving inflammatory response pathways (e.g. IL-23, IL-17, IL-12, IFN-g, TNF) in both cecum and colon. While some microbes were differentially abundant on both LEW and F344 backgrounds (Clostridium, Ruminococcus), other differences were unique to either LEW (Prevotella, Dehalobacterium, Sutterella) or F344 (Akkermansia, rc4-4, Coprococcus, Blautia). Interestingly, many microbes that were strongly correlated with immune dysregulation (e.g. Granulicatella, Staphylococcus and members of family Lachnospiraceae) were not identified by analyzing effects of HLA-B27 alone. Metabolic functions of microbes determined by PICRUSt revealed involvement of similar pathways (e.g. fatty acid and glycan biosynthesis, steroid biosynthesis) in both HLA-B27 Tg LEW and HLA-B27 Tg F344 rats, despite dramatic differences in microbial dysbiosis.

Conclusion: Inter-omic anaylsis of gut microbiota and the host immune response in experimental SpA provides an unprecedented view of the complexity of microbial dysbiosis associated with HLA-B27 and gut inflammation. Perturbation of common metabolic pathways by divergent gut microbiota on different genetic backgrounds during inflammation suggests important functional overlaps that may be key to evoking similar host immune dysregulation. These results suggest that effects of HLA-B27 in the human population will depend on other genetic factors, and that microbial communities and their function may be more important than individual microbes.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/inter-omic-analysis-reveals-functional-relationship-between-diverse-gut-microbiota-and-dysregulated-host-immune-response-in-hla-b27-mediated-experimental-spondyloarthritis/