Gut as an Alternative Entry Route for SARS-CoV-2

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A new international meta-analysis study on published research data involving researchers from Italy, United States, Belgium, Portugal and France has found that the human gut can also serve as an alternative entry for the SARS-CoV-2 virus.

The study findings were published in the peer reviewed Journal of Clinical Medicine. https://www.mdpi.com/2077-0383/11/19/5691

The gut has been proposed as a potential alternative entry route for SARS-CoV-2. This was mainly based on the high levels of SARS-CoV-2 receptor expressed in the gastrointestinal (GI) tract, the observations of GI disorders (such as diarrhea) in some COVID-19 patients and the detection of SARS-CoV-2 RNA in feces.

However, the underlying mechanisms remain poorly understood. It has been proposed that SARS-CoV-2 can productively infect enterocytes, damaging the intestinal barrier and contributing to inflammatory response, which might lead to GI manifestations, including diarrhea. Here, we report a methodological approach to assess the evidence supporting the sequence of events driving SARS-CoV-2 enteric infection up to gut adverse outcomes.

Exploring evidence permits to highlight knowledge gaps and current inconsistencies in the literature and to guide further research. Based on the current insights on SARS-CoV-2 intestinal infection and transmission, we then discuss the potential implication on clinical practice, including on long COVID.

A better understanding of the GI implication in COVID-19 is still needed to improve disease management and could help identify innovative therapies or preventive actions targeting the GI tract.

Current Evidence and Uncertainties of an Active SARS-CoV-2 Enteric Infection

Besides GI symptoms experienced by many COVID-19 patients and SARS-CoV-2 RNA detected in feces, the rationale supporting intestinal infection was also based on the high level of expression in the intestines of the main SARS-CoV-2 cellular gateways: angiotensin converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2).

Enterocytes in the small intestine express the highest levels of ACE2 in the human body [24] and are one of the few human cell types that co-express TMPRSS2 [24], the main cofactor mediating cellular entry [7,25,26]. To evaluate if SARS-CoV-2 can effectively infect enterocytes, we assessed the evidence from the literature, starting with viable SARS-CoV-2 in the gut lumen binding to ACE2 receptors at the apical surface of the enterocytes, cell entry via TMPRSS2 cleavage and replication while antagonizing the antiviral response in order to release new viral particles (Figure 1).

Figure 1. Pathway depicting the proposed sequence of events of a productive SARS-CoV-2 infection in the gut. Virus binding to the ACE2 receptor expressed on enterocytes mediates viral entry inducing an antiviral response that must be antagonized for new virions to be produced. This manuscript will evaluate available published data on the likelihood of their occurrence.

Current Evidence and Uncertainties of SARS-CoV-2 Damaging Intestinal Barrier

SARS-CoV-2 infection was reported to be a cytopathic virus in lung cells triggering cell apoptosis in lung epithelial cells and in lungs of infected mice while lung sections of fatal COVID-19 patients revealed cell death markers [84]. Thus, SARS-CoV-2 has been proposed to induce cell death resulting in disruption of the epithelial monolayer integrity or alterations to tight junctions (TJ), the mucus layer and/or the cellular immune system.

Disruption of the intestinal barrier layers is associated with increased intestinal permeability, also called “leaky gut”, which allows the transfer of commensal or pathogenic bacteria and bacterial components into the lamina propria and later on into the systemic circulation [85] (Figure 2).

Figure 2. Pathway depicting the sequence of events for SARS-CoV-2 enteric production impairing intestinal barrier (AOP422). Evidence is evaluated in the present work to assess the likelihood of the occurrence.

Current Evidence and Uncertainties of SARS-CoV-2 Enteric Infection Contributing to the Inflammatory Response

While productive replication still needs further studies, strong evidence supports SARS-CoV-2 entry in intestinal epithelial cells. There it might trigger a coordinated innate immune response due to the recognition of SARS-CoV-2 associated molecular patterns, similar to that reported in the lung cells [49,95], inducing an antiviral response as described above but also releasing proinflammatory mediators which recruit immune cells to the gut, which in turn secrete cytokines leading to gut inflammation (Figure 3).

Figure 3. Pathway depicting the sequence of events of SARS-CoV-2 enteric infection contributing to the inflammatory response. This manuscript assesses whether evidence supports these events.

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