Dataset Information

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

ABSTRACT:

Objective

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.

Methods

Intestinal contents were collected from wild-type and HLA-B27/β2 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.

Results

An inflammatory cytokine signature and elevated AMP expression during the postweaning period preceded the development of clinical bowel inflammation and dysbiosis in HLA-B27/β2 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/β2 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.

Conclusion

HLA-B27/β2 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/β2 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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Publications

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:BackgroundBased on clinical and genetic associations, axial spondyloarthritis (axSpA) and inflammatory bowel disease (IBD) are suspected to have a linked pathogenesis. Gut dysbiosis, intrinsic to IBD, has also been observed in axSpA. It is, however, not established to what degree gut dysbiosis is associated with axSpA disease severity. The objective of this study was to compare gut dysbiosis frequency between controls, non-radiographic axial spondyloarthritis (nr-axSpA), and ankylosing spondylitis (AS) patients and investigate whether gut dysbiosis is cross-sectionally associated with axSpA disease activity, physical function, mobility, or pain.MethodsGut dysbiosis was assessed by 16SrRNA analysis of feces from 44/88 nr-axSpA/AS patients (ASAS/mNY criteria) without inflammatory bowel disease (IBD) and 46 controls without IBD or rheumatic disease. The GA-map™ Dysbiosis Test was used, grading gut microbiota aberrations on a 1-5 scale, where ≥3 denotes dysbiosis. Proportions with dysbiosis were compared between the groups. Furthermore, standard axSpA measures of disease activity, function, mobility, and pain were compared between patients (nr-axSpA and AS combined) with and without dysbiosis, univariately, and adjusted for relevant confounders (ANCOVA).ResultsGut dysbiosis was more frequent in AS than controls (36% versus 17%, p=0.023), while nr-axSpA (25% dysbiosis) did not differ significantly from either AS or controls. Univariately, most axSpA measures were significantly worse in patients with dysbiosis versus those without: ASDAS-CRP between-group difference 0.6 (95% CI 0.2-0.9); BASDAI 1.6 (0.8-2.4); evaluator's global disease activity assessment (Likert scale 0-4) 0.3 (0.1-0.5), BASFI 1.5 (0.6-2.4), and VAS pain (cm) 1.3 (0.4-2.2). Differences remained significant after adjustment for demographics, lifestyle factors, treatments, gut inflammation (fecal calprotectin ≥50 mg/kg), and gut symptoms, except for VAS pain. BASMI and CRP were not associated with dysbiosis.ConclusionGut dysbiosis, more frequent in AS patients than controls, is associated with worse axSpA disease activity and physical function, seemingly irrespective of both gut inflammation and treatments. This provides further evidence for an important link between disturbances in gastrointestinal homeostasis and axSpA.

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.

Dataset Information

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

Objective

Methods

Results

Conclusion

Publications

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

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