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Perturbed Mucosal Immunity and Dysbiosis Accompany Clinical Disease in a Rat Model of Spondyloarthritis.

ABSTRACT: The HLA-B27/?2 -microglobulin (?2 m)-transgenic (Tg) rat is a leading model of B27-associated spondyloarthritis (SpA), and the disease is dependent on the presence of intestinal bacteria. Previous studies have shown that adult HLA-B27/?2 m-Tg rats have an altered intestinal microbiota. This study sought to better define the age-dependent changes to both mucosal immune function and dysbiosis in this rat model of SpA.Intestinal contents were collected from wild-type and HLA-B27/?2 m-Tg rats postweaning (ages 3 and 6 weeks), at disease onset (age 10 weeks), and after the establishment of disease (ages ?16 weeks). The microbial community structure was determined by 16S ribosomal RNA sequencing and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Mucosal and systemic Th1, Th17, and Treg cell responses were analyzed by flow cytometry, as was the frequency of IgA-coated intestinal bacteria. Intestinal expression of inflammatory cytokines and antimicrobial peptides (AMPs) was determined by qRT-PCR.An inflammatory cytokine signature and elevated AMP expression during the postweaning period preceded the development of clinical bowel inflammation and dysbiosis in HLA-B27/?2 m-Tg rats. An early and sustained expansion of the Th17 cell pool was specifically observed in the cecal and colonic mucosa of HLA-B27/?2 m-Tg rats. Strongly elevated intestinal colonization of Akkermansia muciniphila and an increased frequency of IgA-coated fecal bacteria were significantly associated with expression of HLA-B27 and arthritis development.HLA-B27/?2 m expression in this rat model renders the host hyperresponsive to microbial antigens from infancy. Early activation of innate immunity and expansion of a mucosal Th17 signature are soon followed by dysbiosis in HLA-B27/?2 m-Tg animals. The pathologic processes of perturbed mucosal immunity and dysbiosis strongly merit further study in both prediseased and diseased populations of patients with SpA.

SUBMITTER: Asquith MJ

PROVIDER: S-EPMC5542398 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Perturbed Mucosal Immunity and Dysbiosis Accompany Clinical Disease in a Rat Model of Spondyloarthritis.

Asquith Mark J MJ Stauffer Patrick P Davin Sean S Mitchell Claire C Lin Phoebe P Rosenbaum James T JT

Arthritis & rheumatology (Hoboken, N.J.) 20160901 9

<h4>Objective</h4>The HLA-B27/β2 -microglobulin (β2 m)-transgenic (Tg) rat is a leading model of B27-associated spondyloarthritis (SpA), and the disease is dependent on the presence of intestinal bacteria. Previous studies have shown that adult HLA-B27/β2 m-Tg rats have an altered intestinal microbiota. This study sought to better define the age-dependent changes to both mucosal immune function and dysbiosis in this rat model of SpA.<h4>Methods</h4>Intestinal contents were collected from wild-ty ...[more]

PMID: 26992013

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Project description: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.

Project description:OBJECTIVE:HLA-B27-associated spondyloarthritides are associated with an altered intestinal microbiota and bowel inflammation. We undertook this study to identify HLA-B27-dependent changes in both host and microbial metabolites in the HLA-B27/?2 -microglobulin (?2 m)-transgenic rat and to determine whether microbiota-derived metabolites could impact disease in this major model of spondyloarthritis. METHODS:Cecal contents were collected from Fischer 344 33-3 HLA-B27/?2 m-transgenic rats and wild-type controls at 6 weeks (before disease) and 16 weeks (with active bowel inflammation). Metabolomic profiling was performed by high-throughput gas and liquid chromatography-based mass spectrometry. HLA-B27/?2 m-transgenic rats were treated with the microbial metabolites propionate or butyrate in drinking water for 10 weeks, and disease activity was subsequently assessed. RESULTS:Our screen identified 582 metabolites, of which more than half were significantly altered by HLA-B27 expression at 16 weeks. Both microbial and host metabolites were altered, with multiple pathways affected, including those for amino acid, carbohydrate, xenobiotic, and medium-chain fatty acid metabolism. Differences were even observed at 6 weeks, with up-regulation of histidine, tyrosine, spermidine, N-acetylmuramate, and glycerate in HLA-B27/?2 m-transgenic rats. Administration of the short-chain fatty acid propionate significantly attenuated HLA-B27-associated inflammatory disease, although this was not associated with increased FoxP3+ T cell induction or with altered expression of the immunomodulatory cytokines interleukin-10 (IL-10) or IL-33 or of the tight junction protein zonula occludens 1. HLA-B27 expression was also associated with altered host expression of messenger RNA for the microbial metabolite receptors free fatty acid receptor 2 (FFAR2), FFAR3, and niacin receptor 1. CONCLUSION:HLA-B27 expression profoundly impacts the intestinal metabolome, with changes evident in rats even at age 6 weeks. Critically, we demonstrate that a microbial metabolite, propionate, attenuates development of HLA-B27-associated inflammatory disease. These and other microbiota-derived bioactive mediators may provide novel treatment modalities in HLA-B27-associated spondyloarthritides.

Dataset Information

Perturbed Mucosal Immunity and Dysbiosis Accompany Clinical Disease in a Rat Model of Spondyloarthritis.

Publications

Perturbed Mucosal Immunity and Dysbiosis Accompany Clinical Disease in a Rat Model of Spondyloarthritis.

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