Document Detail


ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation.
MedLine Citation:
PMID:  22837003     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Tatsuo Hashimoto; Thomas Perlot; Ateequr Rehman; Jean Trichereau; Hiroaki Ishiguro; Magdalena Paolino; Verena Sigl; Toshikatsu Hanada; Reiko Hanada; Simone Lipinski; Birgit Wild; Simone M R Camargo; Dustin Singer; Andreas Richter; Keiji Kuba; Akiyoshi Fukamizu; Stefan Schreiber; Hans Clevers; Francois Verrey; Philip Rosenstiel; Josef M Penninger
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-07-25
Journal Detail:
Title:  Nature     Volume:  487     ISSN:  1476-4687     ISO Abbreviation:  Nature     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-27     Completed Date:  2012-08-27     Revised Date:  2012-10-25    
Medline Journal Info:
Nlm Unique ID:  0410462     Medline TA:  Nature     Country:  England    
Other Details:
Languages:  eng     Pagination:  477-81     Citation Subset:  IM    
Affiliation:
IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
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MeSH Terms
Descriptor/Qualifier:
Animals
Biocatalysis
Colitis / drug therapy,  etiology*,  microbiology*,  pathology
Dextran Sulfate
Diarrhea / complications
Dietary Proteins / metabolism,  pharmacology
Female
Gene Deletion
Genetic Predisposition to Disease
Germ-Free Life
Homeostasis
Immunity, Innate
Intestines / microbiology*,  pathology
Male
Malnutrition / complications*,  metabolism
Metagenome*
Mice
Models, Biological
Niacinamide / metabolism,  pharmacology,  therapeutic use
Peptidyl-Dipeptidase A / deficiency,  genetics,  metabolism*
Renin-Angiotensin System / physiology
TOR Serine-Threonine Kinases / metabolism
Trinitrobenzenesulfonic Acid
Tryptophan / metabolism*,  pharmacology,  therapeutic use
Chemical
Reg. No./Substance:
0/Dietary Proteins; 2508-19-2/Trinitrobenzenesulfonic Acid; 73-22-3/Tryptophan; 9042-14-2/Dextran Sulfate; 98-92-0/Niacinamide; EC 2.7.1.1/TOR Serine-Threonine Kinases; EC 2.7.1.1/mTOR protein, mouse; EC 3.4.15.1/Peptidyl-Dipeptidase A; EC 3.4.17.-/angiotensin converting enzyme 2
Comments/Corrections
Comment In:
Nat Rev Gastroenterol Hepatol. 2012 Sep;9(9):490   [PMID:  22868660 ]
Nature. 2012 Jul 26;487(7408):437-9   [PMID:  22836994 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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