TY - JOUR
T1 - Effects of HLA–B27 on Gut Microbiota in Experimental Spondyloarthritis Implicate an Ecological Model of Dysbiosis
AU - Gill, Tejpal
AU - Asquith, Mark
AU - Brooks, Stephen R.
AU - Rosenbaum, James T.
AU - Colbert, Robert A.
N1 - Funding Information:
Supported by the NIH (National Institute of Arthritis, Musculoskeletal and Skin Diseases Intramural Research Program grant Z01-AR-041184 to Dr. Colbert), the Stan and Madelle Rosenfeld Family Trust, the William and Mary Bauman Foundation, the Spondylitis Association of America, and Research to Prevent Blindness (grants to Dr. Rosenbaum). Dr. Asquith is a Jane Bruckel Scholar of the Spondylitis Association of America.
Funding Information:
We thank Maxime Breban for providing the HLA?B27?transgenic Fischer rats and Joel Taurog for providing the HLA?B7?transgenic Lewis rats. We thank Gustavo Gutierrez-Cruz, Kristina Zaal, and Kalyani Mishra for performing RNA sequencing, imaging, and genotyping, respectively, at the NIAMS core facility. Thanks are due to Rob Knight and Justine Debelius at the University of California, San Diego, for performing microbiome sequencing. We also thank Patrick Stauffer and Paul Montgomery at OHSU, and the NIAMS animal facility for providing assistance with the necropsies. The NIH High Performing Computation system Biowulf cluster (http://hpc.nih.gov) was used for analysis.
Publisher Copyright:
© 2017, American College of Rheumatology
PY - 2018/4
Y1 - 2018/4
N2 - 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.
AB - 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.
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U2 - 10.1002/art.40405
DO - 10.1002/art.40405
M3 - Article
C2 - 29287307
AN - SCOPUS:85043307055
SN - 2326-5191
VL - 70
SP - 555
EP - 565
JO - Arthritis and Rheumatology
JF - Arthritis and Rheumatology
IS - 4
ER -