Salt-responsive gut commensal modulates TH17 axis and disease

Nicola Wilck; Mariana G Matus; Sean M Kearney; Scott W Olesen; Kristoffer Forslund; Hendrik Bartolomaeus; Stefanie Haase; Anja Mähler; András Balogh; Lajos Markó; Olga Vvedenskaya; Friedrich H Kleiner; Dmitry Tsvetkov; Lars Klug; Paul I Costea; Shinichi Sunagawa; Lisa Maier; Natalia Rakova; Valentin Schatz; Patrick Neubert; Christian Frätzer; Alexander Krannich; Maik Gollasch; Diana A Grohme; Beatriz F Côrte-Real; Roman G Gerlach; Marijana Basic; Athanasios Typas; Chuan Wu; Jens M Titze; Jonathan Jantsch; Michael Boschmann; Ralf Dechend; Markus Kleinewietfeld; Stefan Kempa; Peer Bork; Ralf A Linker; Eric J Alm; Dominik N Müller

doi:10.1038/nature24628

Salt-responsive gut commensal modulates T_H17 axis and disease

Nature. 2017 Nov 30;551(7682):585-589. doi: 10.1038/nature24628. Epub 2017 Nov 15.

Authors

Nicola Wilck^{1

2

3

4

5}, Mariana G Matus^{6

7}, Sean M Kearney⁶, Scott W Olesen⁶, Kristoffer Forslund⁸, Hendrik Bartolomaeus^{1

2

3

4}, Stefanie Haase⁹, Anja Mähler^{1

5}, András Balogh^{1

2

3

4

5}, Lajos Markó^{1

2

3

4

5}, Olga Vvedenskaya^{3

10

11}, Friedrich H Kleiner¹, Dmitry Tsvetkov^{1

2}, Lars Klug^{1

5}, Paul I Costea⁸, Shinichi Sunagawa^{8

12}, Lisa Maier¹³, Natalia Rakova^{1

9}, Valentin Schatz¹⁴, Patrick Neubert¹⁴, Christian Frätzer¹⁵, Alexander Krannich⁵, Maik Gollasch^{1

2

3}, Diana A Grohme¹⁶, Beatriz F Côrte-Real¹⁷, Roman G Gerlach¹⁸, Marijana Basic¹⁹, Athanasios Typas¹³, Chuan Wu²⁰, Jens M Titze²¹, Jonathan Jantsch¹⁴, Michael Boschmann^{1

5}, Ralf Dechend^{1

2

5}, Markus Kleinewietfeld^{16

17

22}, Stefan Kempa^{3

5

10}, Peer Bork^{3

8

23

24}, Ralf A Linker⁹, Eric J Alm⁶, Dominik N Müller^{1

2

3

4

5}

Affiliations

¹ Experimental and Clinical Research Center, a joint cooperation of Max-Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, 13125 Berlin, Germany.
² Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
³ Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany.
⁴ DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany.
⁵ Berlin Institute of Health (BIH), Berlin, Germany.
⁶ Center for Microbiome Informatics and Therapeutics, and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
⁷ Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
⁸ European Molecular Biology Laboratory, Structural and Computational Biology Unit, 69117 Heidelberg, Germany.
⁹ Department of Neurology, Friedrich-Alexander-University Erlangen-Nuremberg, 91054 Erlangen, Germany.
¹⁰ Integrative Proteomics and Metabolomics Platform, Berlin Institute for Medical Systems Biology BIMSB, 13125 Berlin, Germany.
¹¹ Berlin School of Integrative Oncology, Charité University Medicine Berlin, Berlin, Germany.
¹² Institute of Microbiology, ETH Zurich, 8092 Zurich, Switzerland.
¹³ European Molecular Biology Laboratory, Genome Biology Unit, 69117 Heidelberg, Germany.
¹⁴ Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg, University of Regensburg, 93053 Regensburg, Germany.
¹⁵ Lipidomix GmbH, 13125 Berlin, Germany.
¹⁶ Translational Immunology, Department of Clinical Pathobiochemistry, Medical Faculty Carl Gustav Carus, Technical University of Dresden, 01307 Dresden, Germany.
¹⁷ VIB Laboratory of Translational Immunomodulation, VIB Center for Inflammation Research (IRC), Hasselt University, Campus Diepenbeek, 3590 Diepenbeek, Belgium.
¹⁸ Project Group 5, Robert Koch Institute, 38855 Wernigerode, Germany.
¹⁹ Hannover Medical School, Institute for Laboratory Animal Science and Central Animal Facility, 30625 Hannover, Germany.
²⁰ Experimental Immunology Branch, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.
²¹ Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
²² Center for Regenerative Therapies Dresden (CRTD), 01307 Dresden, Germany.
²³ Molecular Medicine Partnership Unit, University of Heidelberg and European Molecular Biology Laboratory, 69120 Heidelberg, Germany.
²⁴ Department of Bioinformatics, Biocenter, University of Würzburg, 97074 Würzburg, Germany.

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 (T_H17) cells, which can also contribute to hypertension. Induction of T_H17 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 T_H17 cells. In line with these findings, a moderate high-salt challenge in a pilot study in humans reduced intestinal survival of Lactobacillus spp., increased T_H17 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autoimmunity / drug effects
Blood Pressure / drug effects
Disease Models, Animal
Encephalomyelitis, Autoimmune, Experimental / chemically induced
Encephalomyelitis, Autoimmune, Experimental / microbiology
Encephalomyelitis, Autoimmune, Experimental / pathology
Encephalomyelitis, Autoimmune, Experimental / therapy
Feces / microbiology
Gastrointestinal Microbiome / drug effects*
Humans
Hypertension / chemically induced
Indoleacetic Acids / metabolism
Indoles / metabolism
Intestines / cytology
Intestines / drug effects
Intestines / immunology
Intestines / microbiology
Lactobacillus / drug effects*
Lactobacillus / immunology
Lactobacillus / isolation & purification*
Lymphocyte Activation / drug effects
Lymphocyte Count
Male
Mice
Pilot Projects
Sodium Chloride / administration & dosage
Sodium Chloride / pharmacology*
Symbiosis
Th17 Cells / cytology
Th17 Cells / drug effects*
Th17 Cells / immunology*
Tryptophan / metabolism

Substances

Indoleacetic Acids
Indoles
Sodium Chloride
indole-3-lactic acid
indoleacetic acid
Tryptophan

Abstract

Publication types

MeSH terms

Substances

Grants and funding