Could the gut be an alternative route for SARS-CoV-2 entry?

In a recent study published in Journal of Clinical Medicineinvestigators reviewed the intestinal pathophysiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Background

Coronavirus disease 2019 (COVID-19) is primarily a respiratory illness, but it also causes varying degrees of gastrointestinal (GI) symptoms in patients, with symptoms such as diarrhea, nausea, abdominal discomfort, and vomiting. Gastrointestinal distress is considered a direct result of SARS-CoV-2 infection, as viral RNA is detected in the faeces of many patients.

However, the mechanisms underlying diarrhea in COVID-19 are poorly understood. In the current study, researchers evaluated whether the intestine is an alternative route of entry for SARS-CoV-2 and thereby responsible for gastrointestinal disturbances.

Evidence of SARS-CoV-2 intestinal infection

Enterocytes of the small intestine express the highest levels of angiotensin-converting enzyme 2 (ACE2) in humans, and the transmembrane protease serine 2 (TMPRSS2). However, one study did not observe a correlation between ACE2 expression and infectivity of cells in intestinal organoids. Another study observed SARS-CoV-2-infected cells in intestinal organoids regardless of his ACE2 expression on the surface, suggesting an alternative entry mechanism or downregulation of His ACE2 after infection.

Nevertheless, ACE2 knockout (KO) experiments with intestinal organoids indicate that ACE2 is an essential receptor for viral entry. SARS-CoV-2 infection of human intestinal cells has been reported to lead to an innate response mediated by type III interferon (IFN). Interestingly, investigators in one study observed expression profiles of proinflammatory and his IFN-stimulated genes (ISGs) in infected and bystander cells of intestinal organoids.

SARS-CoV-2 replication was less efficient in human intestinal tissue ex vivo, with robust innate responses that elicit type I and type III IFNs. this is, ex vivo Lung tissue in which the virus replicates more efficiently but provokes an attenuated IFN response. Viral RNA has been consistently detected in stool from COVID-19 patients.of viral load It was as high as 10 in feces⁷ copies/g, suggesting that the IFN response did not compromise intestinal infection.

Viral RNA has also been detected in untreated wastewater. In a study in which COVID-19 patients presented with gastrointestinal symptoms and underwent endoscopy, viral RNA was detected in gastric, duodenal, and rectal specimens from critically ill patients. In contrast, viral RNA was detected only in the duodenum in non-severe patients.

Evidence of intestinal barrier damage by SARS-CoV-2 infection

SARS-CoV-2 causes cytopathic effects in the lung and causes apoptosis of epithelial cells. Therefore, SARS-CoV-2 can induce cell death and disrupt the integrity of tight junctions, mucus layers, or epithelial monolayers. When the intestinal barrier layer is disrupted, leaky gut, or intestinal permeability, increases, allowing commensal and other pathogenic bacteria to migrate into the lamina propria and then enter the systemic circulation.

One study reported that cell death in intestinal organoids after SARS-CoV-2 infection was not extensive. In contrast, in vitro Studies with gut-derived organoids revealed an observable disruption of the organoids associated with apoptotic markers. In order for viable SARS-CoV-2 particles to replicate in the gastrointestinal tract, they must reach the intestinal lumen as infectious virions.

Unlike enteric viruses, enveloped viruses can be cleared by exposure to gastric juices and the mucus layer of the gastrointestinal tract. Although SARS-CoV-2 remains stable over a wide range of pH, there is evidence that it lost its infectivity in gastric fluids between pH 1.5 and 3.5. Moreover, rapid inactivation of SARS-CoV-2 by intestinal fluid was observed in the lumen of the colon, suggesting that inactive SARS-CoV-2 particles reach the intestinal lumen. Alternatively, other cells such as lymphocytes or bacteria may transport SARS-CoV-2 to the intestine.

A study observed replication of SARS-CoV-2 in vitro in bacterial growth medium. Fluorescence and electron microscopy showed the presence of SARS-CoV-2 particles within the bacteria. Despite overexpression of ACE2 in the human gut, in vitro SARS-CoV-2 infection of enterocytes, healthy human intestine, may be impermeable to viral entry due to antiviral responses, gastrointestinal fluids, and multiple protective layers of the intestinal barrier.

Nonetheless, there is evidence of intestinal SARS-CoV-2 infection, suggesting that the gut may be permissive to infection under some conditions. needs further research. in vivo SARS-CoV-2 infection of human enterocytes. Viral RNA has been detected in patient stool, but current data on the recovery of infectious viral particles from faeces are conflicting.

in conclusion

Many open questions still permeate the interaction between SARS-CoV-2 and the human gut. For example, it is not yet established whether active SARS-CoV-2 replication occurs in the gut. Moreover, certain conditions may predispose the intestine to SARS-CoV-2 replication, although the underlying mechanisms are not well defined.

Furthermore, it remains unclear whether gastrointestinal symptoms, particularly diarrhea, are a direct result of gastrointestinal SARS-CoV-2 infection or due to local/systemic immune activation. Current evidence moderately supports the concept of the gastrointestinal tract as an alternative portal for SARS-CoV-2 dissemination. Taken together, a better and more comprehensive understanding of the gastrointestinal impact of COVID-19 is needed to improve disease management and design innovative therapies.