ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation

被引:1050
作者
Hashimoto, Tatsuo [1 ,2 ,3 ]
Perlot, Thomas [1 ]
Rehman, Ateequr [4 ]
Trichereau, Jean [1 ]
Ishiguro, Hiroaki [2 ,3 ]
Paolino, Magdalena [1 ]
Sigl, Verena [1 ]
Hanada, Toshikatsu [1 ]
Hanada, Reiko [1 ]
Lipinski, Simone [4 ]
Wild, Birgit [5 ]
Camargo, Simone M. R. [6 ,7 ]
Singer, Dustin [6 ,7 ]
Richter, Andreas [5 ]
Kuba, Keiji [8 ]
Fukamizu, Akiyoshi [9 ]
Schreiber, Stefan [4 ]
Clevers, Hans [10 ,11 ]
Verrey, Francois [6 ,7 ]
Rosenstiel, Philip [4 ]
Penninger, Josef M. [1 ]
机构
[1] Austrian Acad Sci, Inst Mol Biotechnol, IMBA, A-1030 Vienna, Austria
[2] Yokohama City Univ, Grad Sch Med, Dept Med Sci & Cardiorenal Med, Yokohama, Kanagawa 2360004, Japan
[3] Sch Med, Yokohama, Kanagawa 2360004, Japan
[4] Univ Kiel, Inst Clin Mol Biol, D-24105 Kiel, Germany
[5] Univ Vienna, Ctr Ecol, Dept Chem Ecol & Ecosyst Res, A-1090 Vienna, Austria
[6] Univ Zurich, Inst Physiol, CH-8057 Zurich, Switzerland
[7] Univ Zurich, Ctr Integrat Human Physiol, CH-8057 Zurich, Switzerland
[8] Akita Univ, Grad Sch Med, Dept Biol Informat & Expt Therapeut, Akita 0108543, Japan
[9] Univ Tsukuba, Grad Sch Life & Environm Sci, Tsukuba, Ibaraki 3058577, Japan
[10] Royal Netherlands Acad Arts & Sci, Hubrecht Inst, NL-3584 CT Utrecht, Netherlands
[11] Univ Med Ctr Utrecht, NL-3584 CT Utrecht, Netherlands
关键词
ANGIOTENSIN-CONVERTING-ENZYME; MAMMALIAN TARGET; HARTNUP DISORDER; CROHNS-DISEASE; BLOOD-PRESSURE; IN-VIVO; MICE; COLITIS; CARBOXYPEPTIDASE; RAPAMYCIN;
D O I
10.1038/nature11228
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Malnutrition affects up to one billion people in the world and is a major cause of mortality(1,2). In many cases, malnutrition is associated with diarrhoea and intestinal inflammation, further contributing to morbidity and death(2). 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(3), cardiovascular functions(4) and SARS infections(5). 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.
引用
收藏
页码:477 / U89
页数:7
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