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ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation
Open accessAbstract
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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“and ACE2 deficiency has been shown to result in impaired tryptophan homeostasis (Hashimoto et al., 2012).”
From Viral Infections, the Microbiome, and Probiotics (2021) · cites this paper as Hashimoto et al., 2012
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Metadata
- 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
- Venue
- Nature
- Published
- 2012-07-25
- Volume
- 487
- Issue
- 7408
- Pages
- 477-481
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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
- 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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