New Insights Into the Physiopathology of COVID-19: SARS-CoV-2-Associated Gastrointestinal Illness

Abstract

Although SARS-CoV-2 is considered a lung-tropic virus that infects the respiratory tract through binding to the ACE2 cell-surface molecules present on alveolar lungs epithelial cells, gastrointestinal symptoms have been frequently reported in COVID-19 patients. What can be considered an apparent paradox is that these symptoms (e.g., diarrhea), sometimes precede the development of respiratory tract illness as if the breathing apparatus was not its first target during viral dissemination. Recently, evidence was reported that the gut is an active site of replication for SARS-CoV-2. This replication mainly occurs in mature enterocytes expressing the ACE2 viral receptor and TMPRSS4 protease. In this review we question how SARS-CoV-2 can cause intestinal disturbances, whether there are pneumocyte-tropic, enterocyte-tropic and/or dual tropic strains of SARS-CoV-2. We examine two major models: first, that of a virus directly causing damage locally (e.g., by inducing apoptosis of infected enterocytes); secondly, that of indirect effect of the virus (e.g., by inducing changes in the composition of the gut microbiota followed by the induction of an inflammatory process), and suggest that both situations probably occur simultaneously in COVID-19 patients. We eventually discuss the consequences of the virus replication in brush border of intestine on long-distance damages affecting other tissues/organs, particularly lungs.

Age-Related Differences in the Expression of Most Relevant Mediators of SARS-CoV-2 Infection in Human Respiratory and Gastrointestinal Tract

“…In contrast, ACE1 expression was lower in children, and intestinal TMPRSS2 and NRP1 expression was similar in the two study populations. Apparently these data are in contrast with what observed in small intestinal specimens collected from patients affected by inflammatory bowel diseases where similar ACE2 and TMPRSS2 expression was reported comparing pediatric vs. adult subjects (14), or in tissue specimens collected from allergic patients (5) or with data deriving from the analysis of public gene expression datasets (32). It should be considered that these data derived mainly from subjects affected by inflammatory conditions, whereas the strength of our study is the evaluation of a well-characterized population of subjects free of any organic conditions, in which we evaluated the main mediators of SARS-CoV-2 infection.…”

Expression of ACE2, Soluble ACE2, Angiotensin I, Angiotensin II and Angiotensin-(1-7) Is Modulated in COVID-19 Patients

“…The ACE2 expressed at the surface of human alveolar pneumocytes is the receptor for the spike proteins (S1) of SARS-CoV-2 (21)(22)(23). Cell surface expression of ACE2 is however not limited to pneumocytes as the ACE2 gene is differentially expressed in human tissues, offering a broad spectrum of cellular targets to the virus including enterocytes and the arterial and venous endothelial cells (24)(25)(26)(27).…”

Gut Microbiota Dysbiosis and COVID-19: Possible Links

“…Changes in the level of antimicrobial peptides result in modulation in the intestinal microbial population. SARS infection was reported to induce downregulation of ACE2 expression and lead to a reduction in antimicrobial peptides ( Devaux et al., 2021 ). A decrease in the antimicrobial peptides such as α-defensin HD5 promotes the intestinal pathogens to be dominated in the gut and altered the gut microbial composition resulting in gut dysbiosis.…”