Abstract

A Western lifestyle with high salt consumption can lead to hypertension and cardiovascular disease. High salt may additionally drive autoimmunity by inducing T helper 17 (TH17) cells, which can also contribute to hypertension. Induction of TH17 cells depends on gut microbiota; however, the effect of salt on the gut microbiome is unknown. Here we show that high salt intake affects the gut microbiome in mice, particularly by depleting Lactobacillus murinus. Consequently, treatment of mice with L. murinus prevented salt-induced aggravation of actively induced experimental autoimmune encephalomyelitis and salt-sensitive hypertension by modulating TH17 cells. In line with these findings, a moderate high-salt challenge in a pilot study in humans reduced intestinal survival of Lactobacillus spp., increased TH17 cells and increased blood pressure. Our results connect high salt intake to the gut–immune axis and highlight the gut microbiome as a potential therapeutic target to counteract salt-sensitive conditions.

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Acknowledgements

We thank G. N’diaye, I. Kamer, S. Seubert, P. Voss, J. Anders, C. Schmidt, A. Geuzens, R. Hercog and S. Kandels-Lewis for assistance; and J. J. Mullins and F. C. Luft for their support. This study was funded by grants from the German Centre for Cardiovascular Research (DZHK; BER 1.1 VD), the Center for Microbiome Informatics and Therapeutics, and the MetaCardis consortium. D.N.M., J.J. and M.G. were supported by the German Research Foundation (DFG). R.A.L. holds an endowed professorship supported by Novartis Pharma. M.K. was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (640116), by a SALK-grant from the government of Flanders, Belgium and by an Odysseus-grant of the Research Foundation Flanders (FWO), Belgium. L. reuteri was provided by L. Romani.

Author information

Author notes

    • Ralf A. Linker
    • , Eric J. Alm
    •  & Dominik N. Müller

    These authors jointly supervised this work.

Affiliations

  1. Experimental and Clinical Research Center, a joint cooperation of Max-Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, 13125 Berlin, Germany

    • Nicola Wilck
    • , Hendrik Bartolomaeus
    • , Anja Mähler
    • , András Balogh
    • , Lajos Markó
    • , Friedrich H. Kleiner
    • , Dmitry Tsvetkov
    • , Lars Klug
    • , Natalia Rakova
    • , Maik Gollasch
    • , Michael Boschmann
    • , Ralf Dechend
    •  & Dominik N. Müller
  2. Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany

    • Nicola Wilck
    • , Hendrik Bartolomaeus
    • , András Balogh
    • , Lajos Markó
    • , Dmitry Tsvetkov
    • , Maik Gollasch
    • , Ralf Dechend
    •  & Dominik N. Müller
  3. Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany

    • Nicola Wilck
    • , Hendrik Bartolomaeus
    • , András Balogh
    • , Lajos Markó
    • , Olga Vvedenskaya
    • , Maik Gollasch
    • , Stefan Kempa
    • , Peer Bork
    •  & Dominik N. Müller
  4. DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany

    • Nicola Wilck
    • , Hendrik Bartolomaeus
    • , András Balogh
    • , Lajos Markó
    •  & Dominik N. Müller
  5. Berlin Institute of Health (BIH), Berlin, Germany

    • Nicola Wilck
    • , Anja Mähler
    • , András Balogh
    • , Lajos Markó
    • , Lars Klug
    • , Alexander Krannich
    • , Michael Boschmann
    • , Ralf Dechend
    • , Stefan Kempa
    •  & Dominik N. Müller
  6. Center for Microbiome Informatics and Therapeutics, and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Mariana G. Matus
    • , Sean M. Kearney
    • , Scott W. Olesen
    •  & Eric J. Alm
  7. Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Mariana G. Matus
  8. European Molecular Biology Laboratory, Structural and Computational Biology Unit, 69117 Heidelberg, Germany

    • Kristoffer Forslund
    • , Paul I. Costea
    • , Shinichi Sunagawa
    •  & Peer Bork
  9. Department of Neurology, Friedrich-Alexander-University Erlangen-Nuremberg, 91054 Erlangen, Germany

    • Stefanie Haase
    • , Natalia Rakova
    •  & Ralf A. Linker
  10. Integrative Proteomics and Metabolomics Platform, Berlin Institute for Medical Systems Biology BIMSB, 13125 Berlin, Germany

    • Olga Vvedenskaya
    •  & Stefan Kempa
  11. Berlin School of Integrative Oncology, Charité University Medicine Berlin, Berlin, Germany

    • Olga Vvedenskaya
  12. Institute of Microbiology, ETH Zurich, 8092 Zurich, Switzerland

    • Shinichi Sunagawa
  13. European Molecular Biology Laboratory, Genome Biology Unit, 69117 Heidelberg, Germany

    • Lisa Maier
    •  & Athanasios Typas
  14. Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg, University of Regensburg, 93053 Regensburg, Germany

    • Valentin Schatz
    • , Patrick Neubert
    •  & Jonathan Jantsch
  15. Lipidomix GmbH, 13125 Berlin, Germany

    • Christian Frätzer
  16. Translational Immunology, Department of Clinical Pathobiochemistry, Medical Faculty Carl Gustav Carus, Technical University of Dresden, 01307 Dresden, Germany

    • Diana A. Grohme
    •  & Markus Kleinewietfeld
  17. VIB Laboratory of Translational Immunomodulation, VIB Center for Inflammation Research (IRC), Hasselt University, Campus Diepenbeek, 3590 Diepenbeek, Belgium

    • Beatriz F. Côrte-Real
    •  & Markus Kleinewietfeld
  18. Project Group 5, Robert Koch Institute, 38855 Wernigerode, Germany

    • Roman G. Gerlach
  19. Hannover Medical School, Institute for Laboratory Animal Science and Central Animal Facility, 30625 Hannover, Germany

    • Marijana Basic
  20. Experimental Immunology Branch, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA

    • Chuan Wu
  21. Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

    • Jens M. Titze
  22. Center for Regenerative Therapies Dresden (CRTD), 01307 Dresden, Germany

    • Markus Kleinewietfeld
  23. Molecular Medicine Partnership Unit, University of Heidelberg and European Molecular Biology Laboratory, 69120 Heidelberg, Germany

    • Peer Bork
  24. Department of Bioinformatics, Biocenter, University of Würzburg, 97074 Würzburg, Germany

    • Peer Bork

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Contributions

N.W. led and conceived the project, designed and performed most experiments, analysed and interpreted the data. M.G.M., S.W.O. and S.M.K. performed 16S sequencing and data analysis. S.H., D.T., M.Ba. and C.W. performed animal experiments and analysed data. H.B., S.H., A.B., D.A.G. and B.F.C.-R. performed and analysed flow cytometry. L.Mai., S.M.K., V.S., P.N. and R.G.G. performed bacterial growth experiments. O.V. and C.F. performed metabolite analysis with input from A.B. and M.G.M. L.Mar., F.H.K. and L.K. performed 16S qPCR. N.R. performed sodium analyses. K.F. performed metagenomic analyses with contributions from P.I.C. and S.S. M.Bo., R.D. and A.M. conducted the clinical study. A.K. performed statistical analyses. M.G., A.T., J.M.T., S.K., P.B. and J.J. supervised the experiments and analyses. D.N.M., E.J.A., M.K. and R.A.L. conceived the project, supervised the experiments and interpreted the data. N.W. and D.N.M. wrote the manuscript with key editing by E.J.A., R.A.L., M.K. and K.F. and further input from all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Eric J. Alm or Dominik N. Müller.

Reviewer Information Nature thanks T. Coffman, D. A. Relman, H. Wekerle and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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