Abstract

Malnutrition affects up to one billion people in the world and is a major cause of mortality1,2. In many cases, malnutrition is associated with diarrhoea and intestinal inflammation, further contributing to morbidity and death2. The mechanisms by which unbalanced dietary nutrients affect intestinal homeostasis are largely unknown. Here we report that deficiency in murine angiotensin I converting enzyme (peptidyl-dipeptidase A) 2 (Ace2), which encodes a key regulatory enzyme of the renin-angiotensin system (RAS), results in highly increased susceptibility to intestinal inflammation induced by epithelial damage. The RAS is known to be involved in acute lung failure3, cardiovascular functions4 and SARS infections5. Mechanistically, ACE2 has a RAS-independent function, regulating intestinal amino acid homeostasis, expression of antimicrobial peptides, and the ecology of the gut microbiome. Transplantation of the altered microbiota from Ace2 mutant mice into germ-free wild-type hosts was able to transmit the increased propensity to develop severe colitis. ACE2-dependent changes in epithelial immunity and the gut microbiota can be directly regulated by the dietary amino acid tryptophan. Our results identify ACE2 as a key regulator of dietary amino acid homeostasis, innate immunity, gut microbial ecology, and transmissible susceptibility to colitis. These results provide a molecular explanation for how amino acid malnutrition can cause intestinal inflammation and diarrhoea.

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Acknowledgements

We thank all members of our laboratories for discussions. T. Hashimoto was supported by grants from the European Respiratory Society, EuGeneHeart, and SENSHIN. T.P. was supported by a Marie Curie IIF. J.M.P. was supported by grants from IMBA, the Austrian Ministry of Sciences, the Austrian Academy of Sciences, GEN-AU (AustroMouse), an EU ERC Advanced Grant, and the EU network grants EuGeneHeart, ApoSys and INFLA-Care. P.R. was supported by the BMBF Network ‘Systematic genomics of chronic inflammation’, the DFG Cluster of Excellence Inflammation at Interfaces, SPP1399, SFB877, and the DFG project RO1394.

Author information

Author notes

    • Tatsuo Hashimoto
    •  & Thomas Perlot

    These authors contributed equally to this work.

    • Ateequr Rehman

    Present address: Department of Environmental Health Sciences, University Medical Center, Breisacher Strasse 115b, D-79106 Freiburg, Germany.

Affiliations

  1. IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria

    • Tatsuo Hashimoto
    • , Thomas Perlot
    • , Jean Trichereau
    • , Magdalena Paolino
    • , Verena Sigl
    • , Toshikatsu Hanada
    • , Reiko Hanada
    •  & Josef M. Penninger
  2. The Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine and School of Medicine, 2360004 Yokohama, Japan

    • Tatsuo Hashimoto
    •  & Hiroaki Ishiguro
  3. Institute of Clinical Molecular Biology, University of Kiel, Schittenhelmstrasse12, 24105 Kiel, Germany

    • Ateequr Rehman
    • , Simone Lipinski
    • , Stefan Schreiber
    •  & Philip Rosenstiel
  4. Department of Chemical Ecology and Ecosystem Research, Center of Ecology, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria

    • Birgit Wild
    •  & Andreas Richter
  5. Institute of Physiology and Center for Integrative Human Physiology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland

    • Simone M. R. Camargo
    • , Dustin Singer
    •  & Francois Verrey
  6. Department of Biological Informatics and Experimental Therapeutics, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan

    • Keiji Kuba
  7. Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan

    • Akiyoshi Fukamizu
  8. Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, 3584 CT Utrecht, The Netherlands

    • Hans Clevers

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Contributions

T. Hashimoto and T.P. performed most experiments, together with J.T., H.I., M.P., V.S., R.H. and T. Hanada; A. Rehman, P.R., S.L. and S.S. performed sequencing and analysis of the gut microbiome. S.M.R.C., D.S, F.V. and H.C. analysed collectrin and ACE2 expression in gut and kidney. A. Richter and B.W. performed amino acid analysis in serum. K.K. and A.F. provided essential mouse strains. J.M.P. and P.R. coordinated the project, and together with T. Hashimoto and T.P. wrote the manuscript and designed the experiments.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Philip Rosenstiel or Josef M. Penninger.

Supplementary information

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    Supplementary Figures

    This file contains Supplementary Figures 1-26.

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    Supplementary Tables

    This file contains Supplementary Tables 1-6. Please note Table 1 comprises pages 1-38, Table 2 pages 39-69, Table 3 pages 70-108, Table 4 pages 109-137, Table 5 pages 138-178 and Table 6 pages 179-223.

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DOI

https://doi.org/10.1038/nature11228

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