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

  1. Sergio E. Baranzinia,5
  1. aDepartment of Neurology, University of California, San Francisco, CA 94158;
  2. bDivision of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125;
  3. cCenter for Microbiome Innovation, University of California, San Diego, La Jolla, CA 92093;
  4. dDepartment of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
  5. eAdvanced Science Research Center, City University of New York, New York, NY 10031
  1. Edited by Lawrence Steinman, Stanford University School of Medicine, Stanford, CA, and approved August 7, 2017 (received for review June 30, 2017)

Significance

We have experimentally investigated the immunoregulatory effects of human gut microbiota in multiple sclerosis (MS). We have identified specific bacteria that are associated with MS and demonstrated that these bacteria regulate T lymphocyte-mediated adaptive immune responses and contribute to the proinflammatory environment in vitro and in vivo. Thus, our results expand the knowledge of the microbial regulation of immunity and may provide a basis for the development of microbiome-based therapeutics in autoimmune diseases.

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.

Footnotes

  • ?1E.C. and B.B.Y. contributed equally to this work.

  • ?2Present address: Space Biosciences Research Branch, NASA Ames Research Center, Moffett Field, CA 94035.

  • ?3Present address: Department of Neurology, Erasmus University Medical Center, 3015 CE Rotterdam, The Netherlands.

  • ?4Present address: Soonchunhyang University, Cheonan, South Korea.

  • ?5To whom correspondence should be addressed. Email: sergio.baranzini{at}ucsf.edu.
  • 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 http://www.danielhellerman.com/10.7272/Q6N58JH2 and http://www.danielhellerman.com/10.7272/Q6RX997G. Raw data are available upon request.

  • See Commentary on page 10528.

  • This article contains supporting information online at www.danielhellerman.com/lookup/suppl/doi:10.1073/pnas.1711235114/-/DCSupplemental.

Freely available online through the PNAS open access option.

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