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Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models

Cekanaviciute, Egle and Yoo, Bryan B. and Runia, Tessel F. and Debelius, Justine W. and Singh, Sneha and Nelson, Charlotte A. and Kanner, Rachel and Bencosme, Yadira and Lee, Yun Kyung and Hauser, Stephen L. and Crabtree-Hartman, Elizabeth and Katz Sand, Ilana and Gacias, Mar and Zhu, Yungjiao and Casaccia, Patrizia and Cree, Bruce A. C. and Knight, Rob and Mazmanian, Sarkis K. and Baranzini, Sergio E. (2017) Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models. Proceedings of the National Academy of Sciences of the United States of America, 114 (40). pp. 10713-10718. ISSN 0027-8424. PMCID PMC5635915. https://resolver.caltech.edu/CaltechAUTHORS:20170914-194648747

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Abstract

The gut microbiota regulates T cell functions throughout the body. We hypothesized that intestinal bacteria impact the pathogenesis of multiple sclerosis (MS), an autoimmune disorder of the CNS and thus analyzed the microbiomes of 71 MS patients not undergoing treatment and 71 healthy controls. Although no major shifts in microbial community structure were found, we identified specific bacterial taxa that were significantly associated with MS. Akkermansia muciniphila and Acinetobacter calcoaceticus, both increased in MS patients, induced proinflammatory responses in human peripheral blood mononuclear cells and in monocolonized mice. In contrast, Parabacteroides distasonis, which was reduced in MS patients, stimulated antiinflammatory IL-10–expressing human CD4+CD25+ T cells and IL-10+FoxP3+ Tregs in mice. Finally, microbiota transplants from MS patients into germ-free mice resulted in more severe symptoms of experimental autoimmune encephalomyelitis and reduced proportions of IL-10+ Tregs compared with mice “humanized” with microbiota from healthy controls. This study identifies specific human gut bacteria that regulate adaptive autoimmune responses, suggesting therapeutic targeting of the microbiota as a treatment for MS.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://dx.doi.org/10.1073/pnas.1711235114DOIArticle
http://www.pnas.org/content/114/40/10713PublisherArticle
http://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1711235114/-/DCSupplementalPublisherSupporting Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635915PubMed CentralArticle
ORCID:
AuthorORCID
Mazmanian, Sarkis K.0000-0003-2713-1513
Additional Information:© 2017 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND). https://creativecommons.org/licenses/by-nc-nd/4.0/ Edited by Lawrence Steinman, Stanford University School of Medicine, Stanford, CA, and approved August 7, 2017 (received for review June 30, 2017) Published online before print September 11, 2017, doi: 10.1073/pnas.1711235114 We thank the patients who participated in this study and M. Fischbach, S. S. Zamvil, and J. R. Oksenberg for critically reading the manuscript. We also thank the international multiple sclerosis microbiome consortium (iMSMS) for helpful discussions and feedback. This work was supported by the US National Multiple Sclerosis Society, a NIH Institutional Research and Academic Career Development Award Postdoctoral Fellowship, the US Department of Defense, the Valhalla Charitable Foundation, the Emerald Foundation, and Heritage Medical Research Institute. E.C. and B.B.Y. contributed equally to this work. Author contributions: E.C., S.L.H., I.K.S., P.C., B.A.C.C., R. Knight, S.K.M., and S.E.B. designed research; E.C., B.B.Y., T.F.R., S.S., C.A.N., R. Kanner, Y.B., Y.K.L., E.C.-H., I.K.S., M.G., P.C., B.A.C.C., R. Knight, and S.K.M. performed research; R. Knight and S.K.M. contributed new reagents/analytic tools; E.C., B.B.Y., J.W.D., C.A.N., M.G., Y.Z., S.K.M., and S.E.B. analyzed data; and E.C. and S.E.B. wrote the paper. The authors declare no conflict of interest. This article is a PNAS Direct Submission. Data deposition: Normalized datasets related to this paper are available from the UCSF Data Sharing Service (Dash) at https://doi.org/10.7272/Q6N58JH2 and https://doi.org/10.7272/Q6RX997G. Raw data are available upon request. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1711235114/-/DCSupplemental.
Group:Heritage Medical Research Institute, Tianqiao and Chrissy Chen Institute for Neuroscience
Funders:
Funding AgencyGrant Number
National Multiple Sclerosis SocietyUNSPECIFIED
NIH Postdoctoral FellowshipUNSPECIFIED
Department of DefenseUNSPECIFIED
Valhalla Charitable FoundationUNSPECIFIED
Emerald FoundationUNSPECIFIED
Heritage Medical Research InstituteUNSPECIFIED
Subject Keywords:multiple sclerosis; microbiome; autoimmunity
Issue or Number:40
PubMed Central ID:PMC5635915
Record Number:CaltechAUTHORS:20170914-194648747
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170914-194648747
Official Citation:Egle Cekanaviciute, Bryan B. Yoo, Tessel F. Runia, Justine W. Debelius, Sneha Singh, Charlotte A. Nelson, Rachel Kanner, Yadira Bencosme, Yun Kyung Lee, Stephen L. Hauser, Elizabeth Crabtree-Hartman, Ilana Katz Sand, Mar Gacias, Yungjiao Zhu, Patrizia Casaccia, Bruce A. C. Cree, Rob Knight, Sarkis K. Mazmanian, and Sergio E. Baranzini Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models PNAS 2017 114 (40) 10713-10718; published ahead of print September 11, 2017, doi:10.1073/pnas.1711235114
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:81472
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:15 Sep 2017 02:58
Last Modified:03 Oct 2019 18:43

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