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Effects of HLA-B27 on Gut Microbiota in Experimental Spondyloarthritis Implicate an Ecological Model of Dysbiosis.

ABSTRACT: OBJECTIVE:To investigate whether HLA-B27-mediated experimental spondyloarthritis (SpA) is associated with a common gut microbial signature, in order to identify potential drivers of pathogenesis. METHODS:The effects of HLA-B27 on 3 genetic backgrounds, dark agouti (DA), Lewis, and Fischer, were compared, using wild-type littermates and HLA-B7-transgenic Lewis rats as controls. Cecum and colon tissue specimens or contents were collected from the rats at 2, 3-4, and 6-8 months of age, and histologic analysis was performed to assess inflammation, RNA sequencing was used to determine gene expression differences, and 16S ribosomal RNA gene sequencing was used to determine microbiota differences. RESULTS:Both HLA-B27-transgenic Lewis rats and HLA-B27-transgenic Fischer rats developed gut inflammation, while DA rats were resistant to the effects of HLA-B27, and HLA-B7-transgenic rats were not affected. Immune dysregulation was similar in affected Lewis and Fischer rats and was dominated by activation of interleukin-23 (IL-23)/IL-17, interferon, tumor necrosis factor, and IL-1 cytokines and pathways in the colon and cecum, while DA rats exhibited low-level cytokine dysregulation without inflammation. Gut microbial changes in HLA-B27-transgenic rats were strikingly divergent on the 3 different host genetic backgrounds, including different patterns of dysbiosis in HLA-B27-transgenic Lewis and HLA-B27-transgenic Fischer rat strains, with some overlap. Interestingly, DA rats lacked segmented filamentous bacteria that promote CD4+ Th17 cell development, which may explain their resistance to disease. CONCLUSION:The effects of HLA-B27 on gut microbiota and dysbiosis in SpA are highly dependent on the host genetic background and/or environment, despite convergence of dysregulated immune pathways. These results implicate an ecological model of dysbiosis, with the effects of multiple microbes contributing to the aberrant immune response, rather than a single or small number of microbes driving pathogenesis.

SUBMITTER: Gill T

PROVIDER: S-EPMC6101666 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Effects of HLA-B27 on Gut Microbiota in Experimental Spondyloarthritis Implicate an Ecological Model of Dysbiosis.

Gill Tejpal T Asquith Mark M Brooks Stephen R SR Rosenbaum James T JT Colbert Robert A RA

Arthritis & rheumatology (Hoboken, N.J.) 20180307 4

<h4>Objective</h4>To investigate whether HLA-B27-mediated experimental spondyloarthritis (SpA) is associated with a common gut microbial signature, in order to identify potential drivers of pathogenesis.<h4>Methods</h4>The effects of HLA-B27 on 3 genetic backgrounds, dark agouti (DA), Lewis, and Fischer, were compared, using wild-type littermates and HLA-B7-transgenic Lewis rats as controls. Cecum and colon tissue specimens or contents were collected from the rats at 2, 3-4, and 6-8 months of ag ...[more]

PMID: 29287307

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Project description:ObjectiveTo define inflammation-related host-microbe interactions in experimental spondyloarthritis (SpA) using novel inter-omic approaches.MethodsThe relative frequency of gut microbes was determined by 16S ribosomal RNA (rRNA) gene sequencing, and gene expression using RNA-Seq of host tissue. HLA-B27/human β2 -microglobulin-transgenic (HLA-B27-transgenic) and wild-type 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.ResultsInter-omic analysis revealed several gut microbes that were strongly associated with dysregulated cytokines driving inflammatory response pathways, such as interleukin-17 (IL-17), IL-23, IL-17, IL-1, interferon-γ (IFNγ), and tumor necrosis factor (TNF). Many microbes were uniquely associated with inflammation in Lewis or Fischer rats, and one was relevant on both backgrounds. Several microbes that were strongly correlated with immune dysregulation were not differentially abundant in HLA-B27-transgenic compared to wild-type controls. A 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 rats. Inflammation-associated metabolic pathway perturbation (e.g., butanoate, propanoate, lipopolysaccharide, and steroid biosynthesis) was also predicted from both backgrounds.ConclusionInter-omic and network analysis 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, IFNγ, and TNF. Functional similarities between these organisms may explain why animals of 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 the role of dysbiotic microbes in SpA beyond taxonomic profiling.

Project description:ObjectiveWe undertook this study to examine the functional basis for epistasis between endoplasmic reticulum aminopeptidase 1 (ERAP1) and HLA-B27 in experimental spondyloarthritis (SpA).MethodsERAP1-knockout rats were created using genome editing and bred with HLA-B27/human β2 -microglobulin-transgenic (HLA-B27-Tg) rats and HLA-B7-Tg rats. The effects of ERAP1 deficiency on HLA allotypes were determined using immunoprecipitation and immunoblotting, flow cytometry, allogeneic T cell proliferation assays, and gene expression analyses. Animals were examined for clinical features of disease, and tissue was assessed by histology.ResultsERAP1 deficiency increased the ratio of folded to unfolded (β2 m-free) HLA-B27 heavy chains, while having the opposite effect on HLA-B7. Furthermore, in rats with ERAP1 deficiency, HLA-B27 misfolding was reduced, while free HLA-B27 heavy chain dimers on the cell surface and monomers were increased. The effects of ERAP1 deficiency persisted during up-regulation of HLA-B27 and led to a reduction in endoplasmic reticulum stress. ERAP1 deficiency reduced the prevalence of arthritis in HLA-B27-Tg rats by two-thirds without reducing gastrointestinal inflammation. Dendritic cell abnormalities attributed to the presence of HLA-B27, including reduced allogeneic T cell stimulation and loss of CD103-positive/major histocompatibility complex class II-positive cells, were not rescued by ERAP1 deficiency, while excess Il23a up-regulation was mitigated.ConclusionERAP1 deficiency reduced HLA-B27 misfolding and improved folding while having opposing effects on HLA-B7. The finding that HLA-B27-Tg rats had partial protection against SpA in this study is consistent with genetic evidence that loss-of-function and/or reduced expression of ERAP1 reduces the risk of ankylosing spondylitis. Functional studies support the concept that the effects of ERAP1 on HLA-B27 and SpA may be a consequence of how peptides affect the biology of this allotype rather than their role as antigenic determinants.

Dataset Information

Effects of HLA-B27 on Gut Microbiota in Experimental Spondyloarthritis Implicate an Ecological Model of Dysbiosis.

Publications

Effects of HLA-B27 on Gut Microbiota in Experimental Spondyloarthritis Implicate an Ecological Model of Dysbiosis.

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