Cited by 1,271Gut microbiota and healthInflammatory Bowel DiseaseAnimal Nutrition and Physiology

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ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation

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Hashimoto, Tatsuo, Perlot, Thomas, Rehman, Ateequr, Trichereau, Jean, Ishiguro, Hiroaki, Paolino, Magdalena, Sigl, Verena, Hanada, Toshikatsu, Hanada, Reiko, Lipinski, Simone, Wild, Birgit, Camargo, Simone M. R., Singer, Dustin, Richter, Andreas, Kuba, Keiji, Fukamizu, Akiyoshi, Schreiber, Stefan, Clevers, Hans, Verrey, Francois, Rosenstiel, Philip, Penninger, Josef M.·2012·Nature

DOI 10.1038/nature11228PMC PMC7095315

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Abstract

Malnutrition affects up to one billion people in the world and is a major cause of mortality. In many cases, malnutrition is associated with diarrhoea and intestinal inflammation, further contributing to morbidity and death. 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 failure, cardiovascular functions and SARS infections. 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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Authors: Hashimoto, T., Perlot, T., Rehman, A., Trichereau, J., Ishiguro, H., Paolino, M., Sigl, V., Hanada, T., Hanada, R., Lipinski, S., Wild, B., Camargo, S. M. R., Singer, D., Richter, A., Kuba, K., Fukamizu, A., Schreiber, S., Clevers, H., Verrey, F., Rosenstiel, P., & Penninger, J. M.
Affiliations: Institute of Molecular Biotechnology (AT)
University Medical Center Freiburg (DE)
Yokohama City University (JP)
Christian-Albrechts-Universität zu Kiel (DE)
University of Vienna (AT)
University of Zurich (CH)
Akita University (JP)
University of Tsukuba (JP)
Royal Netherlands Academy of Arts and Sciences (NL)
Corresponding author: Rosenstiel, Philip
Penninger, Josef M.
ORCID: Hashimoto, Tatsuo
Rehman, Ateequr
Paolino, Magdalena
Sigl, Verena
Hanada, Toshikatsu
Hanada, Reiko
Lipinski, Simone
Wild, Birgit
Camargo, Simone M. R.
Singer, Dustin
Richter, Andreas
Kuba, Keiji
Fukamizu, Akiyoshi
Schreiber, Stefan
Clevers, Hans
Rosenstiel, Philip
Penninger, Josef M.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2012-07-25
Volume: 487
Issue: 7408
Pages: 477-481
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature11228
PMC: PMC7095315
OpenAlex: W2017614891
Cited by: 1,271
References: 44
Citations by year: 2026: 35 · 2025: 70 · 2024: 96 · 2023: 135 · 2022: 180 · 2021: 229 · 2020: 259 · 2019: 39 · 2018: 44 · 2017: 31 · 2016: 35 · 2015: 28 · 2014: 32 · 2013: 46 · 2012: 11
FWCI: 15.03
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Nature (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion)
Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
Data Archiving and Networked Services (DANS) (submittedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
Zurich Open Repository and Archive (University of Zurich)
Funders: European Respiratory Society
Deutsche Forschungsgemeinschaft (SFB 877, SPP 1399)
Österreichischen Akademie der Wissenschaften
Bundesministerium für Bildung und Forschung
Exzellenzclusters Entzündungsforschung
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Nutrition and Physiology
Keywords: ACE2, angiotensin-converting enzyme 2, protein malnutrition, colitis, intestinal inflammation, gut microbiota, tryptophan metabolism, nicotinamide, renin-angiotensin system, innate immunity, antimicrobial peptides, microbial ecology, epithelial damage, germ-free mice, microbiota transplantation
MeSH terms: Angiotensin-Converting Enzyme 2, Animals, Colitis, Diarrhea, Dietary Proteins, Female, Germ-Free Life, Homeostasis, Immunity, Innate, Intestines, Peptidyl-Dipeptidase A, Male, Models, Biological, Niacinamide, Renin-Angiotensin System, Trinitrobenzenesulfonic Acid, Tryptophan, Dextran Sulfate, Gene Deletion, Genetic Predisposition to Disease, Malnutrition, Mice, Metagenome, Biocatalysis, TOR Serine-Threonine Kinases

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ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation

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