ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation

By Tatsuo Hashimoto, Thomas Perlot, A. Rehman, Jean Trichereau, Hiroaki Ishiguro, Magdalena Paolino, Verena Sigl, Toshikatsu Hanada, Reiko Hanada, S. Lipinski and 11 more. Nature, 2012

1,183 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Cardiology and Cardiovascular Medicine, Physiology

View Paper: https://www.semanticscholar.org/paper/58ec25c2975e8d50fe3c4368b9ca68ba7276f227

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In Cardiology and Cardiovascular Medicine

1. M. Grant
2. J. Zhong
3. Vaibhav B. Patel
4. G. Oudit

In Physiology

1. Curtis Huttenhower
2. B. B. Finlay
3. Rachel N. Carmody
4. Peter J. Turnbaugh
5. Henry J. Haiser
6. Rob Knight
7. Micah Hamady
8. Jeffrey I. Gordon

Citations in the corpus

• Gastrointestinal Manifestations of SARS-CoV-2 Infection and Virus Load in Fecal Samples From a Hong Kong Cohort: Systematic Review and Meta-analysis (2020, neutral): “As ACE2 modulates intestinal inflammation, 25 Gastrointestinal manifestations were also commonly reported during the SARS and MERS outbreaks.”
• Marine Animal Microbiomes: Toward Understanding Host–Microbiome Interactions in a Changing Ocean (2017, background): “In humanized models, major stressors such as malnutrition are related to less physically visible changes in innate immunity, which are linked to microbial ecology (Hashimoto et al., 2012).”
• Alterations in Gut Microbiota of Patients With COVID-19 During Time of Hospitalization (2020, background): “ACE2 is important in controlling intestinal inflammation and gut microbial ecology.(12) With trillions of diverse bacteria dwelling in our gut, the gut microbiome has a myriad of effects on gene regulation of immune response and metabolism.”
• Role of the ACE2/Angiotensin 1–7 axis of the Renin-Angiotensin System in Heart Failure (2016, background): “tional severe acute respiratory syndrome coronavirus receptor, and an amino acid transporter.(34,40,45,46) ACE2 was initially thought to be expressed only in heart, kidney, and testes,(33) but”
• Diet dominates host genotype in shaping the murine gut microbiota (2014, background): “, 2013), and numerous differences have been shown between transgenic animals and matched controls (Couturier-Maillard et al., 2013; Hashimoto et al., 2012; Spor et al., 2011).”
• The Human Microbiome and Child Growth - First 1000 Days and Beyond. (2019, background): “reported that angiotensin I converting enzyme (peptidyl-dipeptidase A) 2 (Ace2) regulates amino acid metabolism, gut microbial homeostasis, and antimicrobial peptide production [73].”
• Intestinal Barrier Dysfunction, LPS Translocation, and Disease Development (2020, background): “Recent studies have also implicated the important role of amino acids in regulating the expression of antimicrobial peptides [34].”
• Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System (2020, background): “Angiotensin-(1-9) attenuates cardiac fibro-”
• Impact of the Gut Microbiota on Intestinal Immunity Mediated by Tryptophan Metabolism (2018, background): “During acute colitis, Trp supplementation protects the epithelial layer and prevents the intestinal inflammation mediated by AhR signaling (Hashimoto et al., 2012).”
• Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. (2013, positive): “In particular, dietary lack of Trp impairs intestinal immunity in mice and alters the gut microbial community (Hashimoto et al., 2012), suggesting that mucosal homeostasis is a multifactorial phenomenon of which Trpmetabolism is an important regulatory component.”