PMID:22837003

Citation	Hashimoto, T, Perlot, T, Rehman, A, Trichereau, J, Ishiguro, H, Paolino, M, Sigl, V, Hanada, T, Hanada, R, Lipinski, S, Wild, B, Camargo, SM, Singer, D, Richter, A, Kuba, K, Fukamizu, A, Schreiber, S, Clevers, H, Verrey, F, Rosenstiel, P and Penninger, JM (2012) ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature 487:477-81
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.
Links	PubMed Online version:10.1038/nature11228
Keywords	Animals; Biocatalysis; Colitis/drug therapy; Colitis/etiology; Colitis/microbiology; Colitis/pathology; Dextran Sulfate; Diarrhea/complications; Dietary Proteins/metabolism; Dietary Proteins/pharmacology; Female; Gene Deletion; Genetic Predisposition to Disease; Germ-Free Life; Homeostasis; Immunity, Innate; Intestines/microbiology; Intestines/pathology; Male; Malnutrition/complications; Malnutrition/metabolism; Metagenome; Mice; Models, Biological; Niacinamide/metabolism; Niacinamide/pharmacology; Niacinamide/therapeutic use; Peptidyl-Dipeptidase A/deficiency; Peptidyl-Dipeptidase A/genetics; Peptidyl-Dipeptidase A/metabolism; Renin-Angiotensin System/physiology; TOR Serine-Threonine Kinases/metabolism; Trinitrobenzenesulfonic Acid; Tryptophan/metabolism; Tryptophan/pharmacology; Tryptophan/therapeutic use
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:ACE2		GO:0015827 : tryptophan transport	ECO:0000315:		P		To demonstrate that the severe colitis in Ace2 deficient mice is due to impaired tryptophan uptake, we provided tryptophan in form of a Gly-Trp dipeptide to bypass the loss of the single amino acid transporter B0AT1. Dietary dipeptidic tryptophan (a Trp+ diet) restored serum tryptophan levels (Supplementary Fig. 16a) and rescued the enhanced DSS-susceptibility of Ace2−/y mice (Fig. 2d–f; Supplementary Fig. 16b–d). Our results show that deficiency of Ace2 causes a critical impairment of local tryptophan homeostasis which alters the susceptibility to intestinal inflammation.	complete CACAO 5530
MOUSE:ACE2	involved_in	GO:0015827: tryptophan transport	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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