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. DOI: https://doi.org/10.1038/nature11228Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-65968 Originally published at: 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 (2012 Supplementary Fig. 4), indicating that these effects are independent of the classical RAS system. Whether ACE inhibition might alter the phenotype of Agtr1a -/-Ace2 -/y mice needs to be further examined. In addition to cleaving AngII, ACE2 exhibits catalytic activity towards a second peptide system, Apelin 15 .However, DSS-induced colitis was not altered in mice carrying genetic mutations in Apelin ( Supplementary Fig. 5) or its receptor Apj (Supplementary Fig. 6). Thus, the catalytic activity of ACE2, essential for its function in the RAS and Apelin cleavage, has no overt role in DSS-induced intestinal inflammation.It had been reported that the RAS can control immune functions 16 . However, in unchallenged Ace2 mutant mice, we did not observe any apparent differences in immune cell populations of the colon and small intestine (insert: "not shown"?). Fig. 10a,b) nor did it affect apoptosis rates of intestinal epithelial cells ( Supplementary Fig. 10a,c).ACE levels were slightly, albeit not significa...

NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer

“…In the mouse, the absence of (a) Rag2 and T-bet, (b) the angiotensin-converting enzyme 2 (ACE2), or (c) the Nod-like receptor pyrin domaincontaining protein 6 is known to predispose to the emergence of transmissible, disease-predisposing commensals (26,36,37). Understanding how the gut mucosa discriminates between disease-predisposing microorganisms and mutualists may provide insights into disease onset and tumor progression in genetically predisposed individuals and their relatives.…”

Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors

“…A similar interaction with ACE2 has been proposed for the L-proline transporter SIT1 the defects of which contributes to iminoglycinuria . The deficiency of ACE2 impairs amino acid absorption in the mouse, in particular of tryptophan, and thereby increases susceptibility to intestinal inflammation (Hashimoto et al 2012). In rodent heart, kidney and aorta, treatment with ACEIs and/or ARBs was shown to increase ACE2 expression (Chappel and Ferrario 2006;Ferrario and Varagic 2010;Igase et al 2005).…”

Multiple Functions of Angiotensin-Converting Enzyme 2 and Its Relevance in Cardiovascular Diseases

“…37, 90 In addition to Hartnup's disorder, a recent study by our group revealed that ACE2 regulates intestinal epithelial immunity by controlling amino acid homeostasis, expression of antimicrobial peptides, and the ecology of the gut microbiome. 91 The finding can molecularly explain why amino acid malnutrition can cause intestinal inflammation and diarrhea. Because such RAS-independent functions of ACE2 have not yet been observed in cardiovascular systems, such as hearts, kidneys, and blood vessels, further studies are warranted.…”