title: ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation.
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.
authors: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
authors: Tatsuo
authors: T
authors: Hashimoto
authors: Thomas
authors: T
authors: Perlot
authors: Ateequr
authors: A
authors: Rehman
authors: Jean
authors: J
authors: Trichereau
authors: Hiroaki
authors: H
authors: Ishiguro
authors: Magdalena
authors: M
authors: Paolino
authors: Verena
authors: V
authors: Sigl
authors: Toshikatsu
authors: T
authors: Hanada
authors: Reiko
authors: R
authors: Hanada
authors: Simone
authors: S
authors: Lipinski
authors: Birgit
authors: B
authors: Wild
authors: Simone M R
authors: SM
authors: Camargo
authors: Dustin
authors: D
authors: Singer
authors: Andreas
authors: A
authors: Richter
authors: Keiji
authors: K
authors: Kuba
authors: Akiyoshi
authors: A
authors: Fukamizu
authors: Stefan
authors: S
authors: Schreiber
authors: Hans
authors: H
authors: Clevers
authors: Francois
authors: F
authors: Verrey
authors: Philip
authors: P
authors: Rosenstiel
authors: Josef M
authors: JM
authors: Penninger
mesh_terms: D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D055162:Biocatalysis; D003092:Colitis / Q000188:drug therapy / Q000209:etiology* / Q000382:microbiology* / Q000473:pathology; D016264:Dextran Sulfate; D003967:Diarrhea / Q000150:complications; D004044:Dietary Proteins / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D005856:Germ-Free Life; D006706:Homeostasis; D007113:Immunity, Innate; D007422:Intestines / Q000382:microbiology* / Q000473:pathology; D008297:Male; D044342:Malnutrition / Q000150:complications* / Q000378:metabolism; D054892:Metagenome; D051379:Mice; D008954:Models, Biological; D009536:Niacinamide / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D007703:Peptidyl-Dipeptidase A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid; D014364:Tryptophan / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D004044:Dietary Proteins; D009536:Niacinamide; D014364:Tryptophan; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2