Publication Date:
2012-07-28
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- England -- Nature. 2012 Jul 25;487(7408):477-81. doi: 10.1038/nature11228.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22837003" target="_blank"〉PubMed〈/a〉
Keywords:
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
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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