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Arthritis Rheumatol. 2019 Jun 19. doi: 10.1002/art.41018. [Epub ahead of print]

Novel Inter-omic Analysis Reveals Relationships Between Diverse Gut Microbiota and Host Immune Dysregulation in HLA-B27-Induced Experimental Spondyloarthritis.

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Pediatric Translational Research Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD.
Biodata Mining and Discovery Section, Office of Science and Technology, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD.
Division of Arthritis and Rheumatic Diseases, Oregon Health and Science University, Portland, OR.
Legacy Devers Eye Institute, Oregon Health and Science University, Portland, OR.



To define inflammation-related host-microbe interactions in experimental spondyloarthritis using novel inter-omic approaches.


The relative frequency of gut microbes was determined by 16S rRNA gene sequencing, and gene expression by RNA-seq of host tissue. HLA-B27/human β2 -microglobulin transgenic (HLA-B27 TG) and wild type (WT) rats from Dark Agouti, Lewis, and Fischer backgrounds were used. Inter-omic analyses using Cytoscape were employed to identify relevant relationships. PICRUSt was used to predict microbial functions based on known metagenomic profiles.


Inter-omic analysis revealed several gut microbes microbes strongly associated with dysregulated cytokines driving inflammatory response pathways (e.g. IL-23, IL-17, IL-1, IFN-γ, TNF). Many microbes were uniquely associated with inflammation in Lewis or Fischer rats, and one was relevant on both backgrounds. Several microbes strongly correlated with immune dysregulation were not differentially abundant in HLA-B27 TG compared to WT controls. Multi-omic network analysis revealed non-overlapping clusters of microbes in Lewis and Fischer rats that were strongly linked to overlapping dysregulated immune/inflammatory genes. Prevotella, Clostridiales, and Blautia were important in Lewis rats, while Akkermansia muciniphila and members of the Lachnospiraceae family dominated in Fischer animals. Inflammation-associated metabolic pathway perturbation (e.g. butanoate, propanoate, LPS, and steroid biosynthesis) was also predicted from both backgrounds.


Inter-omic and network anaylsis of gut microbes and the host immune response in experimental SpA provides an unprecedented view of organisms strongly linked to dysregulated IL-23, IL-17, IL-1, IFN-γ, and TNF pathways. Functional similarities between these organisms may explain why different genetic backgrounds exhibit common patterns of immune dysregulation, possibly through perturbation of similar metabolic pathways. These results highlight the power of linking analyses of gut microbiota with the host immune response to gain insights into role of dysbiotic microbes in SpA beyond taxonomic profiling. This article is protected by copyright. All rights reserved.


HLA-B27; Spondyloarthritis (SpA); candidate causal microbes; host genetics; inflammation; inter-omic analysis; metabolome; microbiome; multi-omic network analysis


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