@article{57cf3fc149a1441890c97aad53703b50,
title = "Translocation of a gut pathobiont drives autoimmunity in mice and humans",
abstract = "Despite multiple associations between the microbiota and immune diseases, their role in autoimmunity is poorly understood. We found that translocation of a gut pathobiont, Enterococcus gallinarum, to the liver and other systemic tissues triggers autoimmune responses in a genetic background predisposing to autoimmunity. Antibiotic treatment prevented mortality in this model, suppressed growth of E. gallinarum in tissues, and eliminated pathogenic autoantibodies and T cells. Hepatocyte–E. gallinarum cocultures induced autoimmune-promoting factors. Pathobiont translocation in monocolonized and autoimmune-prone mice induced autoantibodies and caused mortality, which could be prevented by an intramuscular vaccine targeting the pathobiont. E. gallinarum–specific DNA was recovered from liver biopsies of autoimmune patients, and cocultures with human hepatocytes replicated the murine findings; hence, similar processes apparently occur in susceptible humans. These discoveries show that a gut pathobiont can translocate and promote autoimmunity in genetically predisposed hosts.",
author = "{Manfredo Vieira}, S. and M. Hiltensperger and V. Kumar and D. Zegarra-Ruiz and C. Dehner and N. Khan and Costa, {F. R.C.} and E. Tiniakou and T. Greiling and W. Ruff and A. Barbieri and C. Kriegel and Mehta, {S. S.} and Knight, {J. R.} and D. Jain and Goodman, {A. L.} and Kriegel, {M. A.}",
note = "Funding Information: We thank all patients enrolled under the IRB protocols 1408014402 and 1602017150 (ClinicalTrials.gov identifier NCT02394964) who have participated in this study, as well as K. DeFrancesco and I. Matos for patient recruitment at the Yale Center for Clinical Investigation, which is supported by CTSA grant UL1 RR024139 from the National Center for Research Resources, the National Center for Advancing Translational Science, and the NIH Roadmap for Medical Research. We also thank D. Assis, J. Boyer, and the Yale Liver Center for contributions of liver biopsy material; J. Galan for provision of S. typhimurium; J. Sterpka for technical assistance; O. Pagovich for initial antibiotics experiments; J. Weinstein for assistance with Tfh studies; N. Palm for use of an anaerobic chamber; M. Tokuyama and A. Iwasaki for contributing ERV anti-gp70 antibodies for ERV and ERV IC ELISAs; and E. Meffre, J. Craft, and G. Eberl for critically reading the manuscript. S.M.V. and M.A.K. are inventors on a patent application filed by Yale University related to the use of antibiotics and commensal vaccination to treat autoimmunity (U.S. Provisional Patent Application 62/448,510). Supported by NIH grants K08AI095318, R01AI118855, T32AI07019, and T32DK007017-39; Yale Rheumatic Diseases Research Core (NIH grant P30 AR053495); the Yale Liver Center (NIH grant P30 DK34989); Women{\textquoteright}s Health Research at Yale; the O{\textquoteright}Brien Center at Yale (NIH grant P30DK079310); the Arthritis National Research Foundation; the Arthritis Foundation; and the Lupus Research Institute. Author contributions: S.M.V. designed, performed, and analyzed all murine, gnotobiotic, and human experiments; M.H., D.Z.R., N.K., F.R.C.C., E.T., T.G., and C.K. assisted in murine experiments including gnotobiotics; S.M.V., F.R.C.C., and D.Z.R. performed translocation and barrier function experiments; V.K., C.D., and T.G. were involved in consenting, recruiting, and sampling human study subjects; V.K., A.B., and D.J. obtained all liver biopsy samples; S.M.V. processed and analyzed data related to human material; S.M.V., V.K., C.D., A.B., and D.J. performed histopathologic studies and scoring; S.M.V. and C.D. performed FISH, immunofluorescence staining, and confocal microscopy; S.M.V., V.K., and W.R. performed 16S rDNA sequencing, data processing, and analysis; A.L.G. assisted in microbiologic studies and bioinformatics related to 16S rDNA sequencing; S.M.V. and S.S.M. processed and analyzed the RNA sequencing data; S.S.M. and J.R.K. assembled the bacterial genome; S.M.V. and S.S.M. analyzed the genome; S.M.V. produced the chemical structures drawing and biochemical pathway; S.M.V. and M.A.K. wrote the manuscript with input from all authors; M.A.K. conceived the study and supervised the project; and S.M.V. and M.A.K. participated in design and interpretation of all experiments. All data to understand and assess the conclusions of this research are available in the main text and supplementary materials, as well as via the following repositories: Whole-genome shotgun sequences have been deposited at DDBJ/ENA/GenBank under accession number PPHK00000000. The version described in this paper is version PPHK01000000. RNA-seq and 16S rRNA sequences have been deposited with the European Bioinformatics Institute under accession numbers PRJEB24586 and PRJEB24587, respectively. Publisher Copyright: {\textcopyright} 2017 The Authors.",
year = "2018",
month = mar,
day = "9",
doi = "10.1126/science.aar7201",
language = "English (US)",
volume = "359",
pages = "1156--1161",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6380",
}