MINIREVIEW: Gastrointestinal clinical presentations as well as expression and functional relevance of ACE2 in COVID-19

Summary and Translation: Federica La Russa; Revision: Giulia Peserico

In this minireview, the autors summarize the current knowledge about the possible correlation between ACE2 expression levels and gastrointestinal manifestations of COVID-19.

SARS-CoV2, a seventh identified coronavirus, has caused pandemic cases of human COVID-19 infections worldwide. In adults, COVID-19 infections are clinically characterized by fever, cough and dyspnea, whereas less common symptoms include gastrointestinal alterations such as diarrhea, nausea and vomiting [1].

In contrast to adults, manifestation in children might be dramatically different as suggested by a study conducted by Xu et al. on ten young patients hospitalized after being tested positive [2]. Among them, one child was asymptomatic, whereas other children presented fever (seven), cough (five), sore throat (four), nasal congestion (two) and diarrhea (three). None of the children showed other clinical signs typically observed in adults such as lethargy, muscle ache, headache, nausea, vomiting and disorientation. Interestingly, no pneumonia and only minor signs of lung distress were revealed by Chest X-ray and CT scans, thus suggesting a milder clinical respiratory manifestation. Further, blood count, urine and stool analyses, coagulation function, blood chemistry and infection biomarkers resulted within normal ranges or slightly altered in all but one child, in strong contrast to what observed in adults. In this study, chronological testing of viral excretion from respiratory and gastrointestinal tracts was also performed by RT-PCR (C_t method). All patients tested positive at one point in time, with eight out of ten being also positive in rectal swab. Of note, rectal swab remained positive even after the nasopharyngeal testing had become negative, and the children were already asymptomatic. This suggest viral shedding from the digestive tract might be greater (and longer lasting) than that from the respiratory tract, thus opening to the possibility of fecal-oral transmission [1;3].

In the light of this, looking at the cell-specific distribution of the human cell receptor angiotensin-converting enzyme 2 (ACE2) might prove instrumental to clarify mechanisms of transmission. ACE2 is an enzyme better known for catalyzing the cleavage of angiotensin II (vasoconstrictor) to angiotensin 1-7 (vasodilator) and, due to its role in maintaining cardiovascular physiology, identified as a target for treating cardiovascular diseases [4]. More importantly, SARS-CoV2 binds to ACE2 as well as causing multiorgan failure. A recent study by Zou et al. reveals the receptor expression in various human cell types combining published single-cell RNA sequencing data. Here cell type with a > 1% proportion of ACE2⁺ cells were considered high risk targets, thus proving hints for potential mechanisms of transmission. Based on the defined threshold (proportion of ACE2⁺ cells), respiratory and ileal epithelial cells resulted among the cells with the highest expression (2% and 30%, respectively). Of note, gene expression was also confirmed at the protein level for both gastrointestinal and respiratory tracts [2].

ACE2 expression at the gastrointestinal level begs the question to whether and what extent this is of any functional relevance in the gut. An interesting perspective is proposed in an Editorial by Gao et al. with the possibility of a lung-gut crosstalk in COVID-19. Although not systematically tested, the hypothesis is that alterations in ACE2 function in the gut might affect intestinal microbiome, and result in a negative impact to the respiratory system. Of note, patients with respiratory infections generally have primary or secondary gut dysfunctions, and this is usually accompanied by more sever clinical course of disease. Further, a positive effect of microbiome modulation has been observed in studies regarding infectious diseases affecting the respiratory tract. Interestingly, this therapeutic strategy has been endorsed by the China’s National Health Commission and National Administration of Traditional Chinese Medicine (5^th edition), which proposed the recommendation to supply probiotics to severe COVID-19 patients.

In conclusion, gastrointestinal alterations are relevant to COVID-19 to different extent in adult and children. Careful consideration is required both in terms of evaluation of clinical presentations, to limit further (fecal-oral) spread of the infection, as well as of potential new therapeutic avenues (including ACE2 inhibitors -as proposed in other publications- and microbial manipulation).