ACE2 imbalance as a key player for the poor outcomes in COVID-19 patients with age-related comorbidities - Role of gut microbiota dysbiosis

Abstract

Coronavirus disease 19 (COVID-19) is a pandemic condition caused by the new coronavirus SARS-CoV-2. The typical symptoms are fever, cough, shortness of breath, evolving to a clinical picture of pneumonia and, ultimately, death. Nausea and diarrhea are equally frequent, suggesting viral infection or transmission via the gastrointestinal-enteric system. SARS-CoV-2 infects human cells by using angiotensin converting enzyme 2 (ACE2) as a receptor, which is cleaved by transmembrane proteases during host cells infection, thus reducing its activities. ACE2 is a relevant player in the renin-angiotensin system (RAS), counterbalancing the deleterious effects of angiotensin II. Furthermore, intestinal ACE2 functions as a chaperone for the aminoacid transporter B⁰AT1. It has been suggested that B⁰AT1/ACE2 complex in the intestinal epithelium regulates gut microbiota (GM) composition and function, with important repercussions on local and systemic immune responses against pathogenic agents, namely virus. Notably, productive infection of SARS-CoV-2 in ACE2⁺ mature human enterocytes and patients' GM dysbiosis was recently demonstrated. This review outlines the evidence linking abnormal ACE2 functions with the poor outcomes (higher disease severity and mortality rate) in COVID-19 patients with pre-existing age-related comorbidities and addresses a possible role for GM dysbiosis. The article culminates with the therapeutics opportunities based on these pathways.

Keywords: ACE2; Age-related diseases; COVID-19; Gut microbiota dysbiosis; Poor outcomes; SARS-CoV-2.

Fig. 1

Putative association between ACE2 shedding after SARS-CoV-2 infection and the poor outcomes in elderly COVID-19 patients with pre-existing age-related cardiovascular, cardiometabolic and cardiorenal diseases. An imbalanced Ang II/Ang 1-7 ratio, due to the loss of ACE2 protective function, favors Ang II-AT1R signaling and subsequent vasoconstrictive, pro-hypertensive, pro-oxidant, pro-inflammatory and pro-fibrotic events (RAS-dependent pathway, right). Furthermore, ACE2 shedding may also dictate a dysbiotic gut condition (RAS-independent pathway, left). Briefly, loss of ACE2 integrity, a chaperone of intestinal B⁰AT1 carrier, may negatively impact neutral amino acids transport with subsequent mTOR-dependent AMPs disrupted synthesis, altered local immunity and gut microbiota dysbiosis. Concurrently, increased Ang II levels may also impair GM composition and function. Altered gut barrier permeability may add an extra-level of complexity to this scenario, allowing the translocation of local microbiota components to the bloodstream, including resident SARS-CoV-2 viral particles. Whether these events foster SARS-CoV-2 fecal-oral transmission deserves further studies. Nevertheless, such deleterious cascades may aggravate the pre-existing gut dysbiosis, systemic inflammation and impaired immune response in cardiovascular, cardiometabolic and cardiorenal patients, rendering them less suited to manage COVID-19 infection.