The Role of Angiotensin Converting Enzyme 2 in Modulating Gut Microbiota, Intestinal Inflammation, and Coronavirus Infection

Abstract

The role of angiotensin converting enzyme 2 has expanded from regulating the renin angiotensin system to regulating intestinal amino acid homeostasis and the gut microbiome. Recently, angiotensin converting enzyme 2 was identified as a primary receptor for severe acute respiratory syndrome coronaviruses 1 and 2 being expressed in multiple tissues including the luminal surface of the gut. In this brief perspective, we examine the role of angiotensin converting enzyme 2 as the receptor for severe acute respiratory syndrome coronavirus 2 and the impact of coronavirus disease 19 infection on the gut microbiome and on the gut epithelium.

Keywords: ACE2; Gut Microbiota; SAR-CoV-2.

Figure 1

The dysregulated RAS in the gut of patients with COVID-19. All RAS components are recapitulated locally in the gut. ACE2 serves as the receptor for SARS-CoV-2 to promote viral infection and replication. Spike S-protein of SARS-CoV-2 binding to the extracellular domain of ACE2 can lead to internalization of ACE2/B⁰AT1. B⁰AT1 serves as an amino acid transporter for tryptophan. Tryptophan stimulates enteroendocrine L cells to release GLP-1 and GIP, key incretins that regulate pancreatic insulin-producing β cells and inhibit glucagon-producing α cells thereby modulating plasma glucose levels. SARS-CoV-2 by down-regulating intestinal ACE2-B⁰AT1 would disrupt glucose and sodium homeostasis. Reduced levels of ACE2 could result in a dysbiotic gut by diminishing the generation of Ang 1-7 and activation of the Mas receptor, resulting in unimpeded and increased absorption of glucose from the gut. Dysbiosis can lead to disruption of the gut barrier, resulting in release of microbial products into the circulation. These changes in an already compromised patient with COVID-19 can lead to enhanced systemic inflammation.

Figure 2

Individuals with COVID-19 infection might experience diarrhea, nausea, and vomiting. This can lead to viral shedding in the stool, ultimately contributing to fecal–oral transmission of SARS-CoV-2. An individual’s gut microbiome can determine susceptibility to IBD and perhaps COVID-19 infection. In the small intestine, reduced tryptophan uptake by epithelial cells results in diminished release of antimicrobial peptides via reduced mTOR activation. In the large intestinal epithelial cells, the dysbiotic gut microbiome results in increased release of proinflammatory cytokines, loss of tight junction formation, and changes in mucosal cell autophagy.