• How Does SARS-CoV-2 Binding to ACE2 Alter the Gut to Promote Systemic Inflammation?

How Does SARS-CoV-2 Binding to ACE2 Alter the Gut to Promote Systemic Inflammation?

SARS-CoV-2, by down-regulating intestinal angiotensin converting enzyme 2 (ACE2), alters the intestinal microbiome and promotes leaky gut syndrome, increasing plasma bacterial lipopolysaccharides and/or peptidoglycans to promote systemic inflammation, Josef M. Penninger et al explain in a Brief Review in the January issue of Gastroenterology. Strategies to increase intestinal ACE2 might be developed to improve outcomes in patients with COVID-19.

The dysregulated RAS in the gut of patients with COVID-19. The spike S-protein of SARS-CoV-2 binds to the extracellular domain of ACE2 and is internalized. BOAT1 serves as an amino acid transporter for tryptophan, which stimulates enteroendocrine L cells to release GLP-1 and GIPincretins that regulate pancreatic insulin-producing β cells and inhibit glucagon-producing α cells to regulate plasma glucose levels. Reduced levels of ACE2 could result in gut dysbiosis by reducing generation of Ang 1-7 and activation of the Mas receptor, resulting in 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.

ACE2 not only regulates the renin angiotensin system (RAS), but also intestinal amino acid homeostasis and the gut microbiome. ACE2 is a primary receptor for SARS-CoV-2, expressed in multiple tissues including the heart, kidney, lungs, and gut. Penninger et al examine how the effects of the virus on ACE2 alter the gut microbiome and epithelium to promote systemic infection.

They review the mechanisms by which ACE2 regulates the RAS, a hormonal circuit that controls extracellular fluid volume and blood pressure, and how SARS viruses downregulates expression of ACE2 in multiple tissues to promote pulmonary edema and heart, kidney, and lung tissue damage.

Penninger et al explain that in the intestine, ACE2 stabilizes neutral amino acid transporters, such as BOAT1, so loss of ACE2 compromises intestinal uptake of certain dietary amino acids, such as tryptophan, which helps regulate immunity. ACE2-knockout mice have alterations to the gut microbiota and develop more severe dextran sulfate sodium–induced colitis than wild-type mice. The authors propose that down-regulation of ACE2 by SARS-CoV-2 could account for the multi-organ failure that occurs in patients with COVID-19, and restoration of ACE2 is a rational therapeutic strategy.

The Review article covers the gastrointestinal manifestations of SARS-CoV-2 infection. Diarrhea is common in patients with SARS infections, although intestinal biopsies reveal minimal architectural disruption with no villous atrophy of the colonic epithelium. The pooled prevalence of SARS-CoV-2 RNA in stool samples from patients with COVID-19 was 48.1%. SARS-CoV-2 alters the fecal microbiomes of hospitalized patients, depleting commensal species. Penninger propose that exposure to SARS-CoV-2 might have long-lasting deleterious effects to the gut microbiome.

Penninger et al also review the associations between ACE2 and colitis. ACE2 expression is reduced by 60% in the inflamed ileum of patients with Crohn’s disease, compared with healthy individuals. However, patients with inflammatory bowel diseases (IBD) have not been found to be more susceptible to SARS-CoV-2 infection. Increasing age, comorbidities, and use of corticosteroids and other anti-inflammatory agents correlated with severe COVID-19 in patients with IBD, whereas treatment with tumor necrosis factor (TNF) antagonists did not.

Penninger et al propose a model of SARS-Cov-2 interactions with ACE2 and the RAS in the gut to promote intestinal permeability and systemic inflammation, and even alter glucose homeostasis (see Figure). The authors propose a model by which leaky gut and microbial dysbiosis contribute to the cytokine storm in patients with severe COVID-19.

The Review discusses mechanisms by which restoration of epithelial ACE2 might restore balance to the disturbed RAS and intestinal amino acid uptake to benefit patients with COVID-19. Recombinant human ACE2 is being tested in a clinical trial for its ability to block viral entry and decrease viral replication in patients with COVID-19. A phase 2a study found that recombinant ACE2 was well tolerated, producing significant improvements in cardiac output and pulmonary vascular resistance. Infusion of the protein was associated with reduced plasma markers of inflammation within 2–4 hours and with increases in plasma SOD2 at 2 weeks.