Ace2 deficiency in mice resulted in highly increased susceptibility to intestinal inflammation, driven by altered gut microbial ecology and impaired dietary amino acid homeostasis.
ACE2 has a RAS-independent function in regulating intestinal amino acid homeostasis and the gut microbiome, explaining how protein malnutrition can lead to intestinal inflammation.
Mutations in angiotensin-converting enzyme 2 are shown to predispose mice to colitis as a consequence of neutral amino acid malabsorption and a change in the resident microbiota; these results could explain how protein malnutrition — affecting up to one billion people — leads to intestinal inflammation. Malnutrition affects many millions of people in the developing world and remains a problem in wealthy nations, especially for disadvantaged groups. In many cases, it is the associated diarrhoea and intestinal inflammation that cause morbidity and death. A study published in this issue presents a molecular explanation for the increased susceptibility to intestinal inflammation in malnutrition. Angiotensin converting enzyme 2 (ACE2), which has a central role in blood-pressure regulation and has been implicated in diabetes, heart failure and viral infection, is shown to influence dietary amino-acid homeostasis, innate immunity, gut microbial ecology and susceptibility to colitis. Mice deficient in this enzyme show impaired tryptophan metabolism and develop colitis, which is alleviated by dietary tryptophan and its metabolite, nicotinamide. This surprising result explains nutritional effects that have been known for centuries and provides a molecular link between malnutrition and the intestinal microbiome. Malnutrition affects up to one billion people in the world and is a major cause of mortality1,2. In many cases, malnutrition is associated with diarrhoea and intestinal inflammation, further contributing to morbidity and death2. 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 failure3, cardiovascular functions4 and SARS infections5. 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.
Hashimoto et al. (Tue,) conducted a other in Intestinal inflammation and colitis. Ace2 deficiency vs. Wild-type was evaluated on Susceptibility to intestinal inflammation. Ace2 deficiency in mice resulted in highly increased susceptibility to intestinal inflammation, driven by altered gut microbial ecology and impaired dietary amino acid homeostasis.