There has been increasing evidence that the coronavirus Sars-CoV-2 can also affect the intestine. Researchers have now used organoids to investigate exactly how this works – mini-versions of the human intestinal tract grown in the laboratory. It was shown that the virus penetrates and increases in the mature and immature enterocytes of the intestinal wall. These cells play a crucial role in the absorption of nutrients and water from food and are the most common cell type in the small intestine. Infection of these cells explains why around a third of Covid-19 patients suffer from diarrhea and other digestive disorders.
As the corona pandemic continues, it is becoming increasingly clear that the Sars-CoV-2 virus affects far more areas in our body than just the airways and lungs. Observations on patients have increasingly shown that cardiovascular damage can also occur in connection with Covid-19, that the infection interferes with blood clotting, promotes thrombosis and embolism and that the nerves can also be attacked. In about a third of Covid-19 patients, the infection is accompanied by gastrointestinal symptoms, especially diarrhea and nausea. Viruses have also been detected in stool samples. This has long been an indication that Sars-CoV-2 can also affect the intestinal tract, especially since the cells on the inside of the intestine also have so-called ACE2 receptors – proteins that serve the virus as docking points and “door openers” into the cell.
Intestinal organoids in an infection test
Mart Lamers from the Erasmus Medical Center in Rotterdam and his colleagues have now investigated which cells in the intestine are actually affected by Sars-CoV-2 and to what extent. To do this, they used a relatively new achievement in biomedicine: organoids. These are mini-versions of human organs grown in the laboratory, which are mostly used from precursor cells of the cell types present in the tissues of these organs. Usually three-dimensional “scaffolds” made of special hydrogels ensure that these mini-organs also get the right shape. “The organoids of the human small intestine are grown from stem cells of the intestinal epithelium and contain all cell types of the real intestinal mucosa,” explains Lamers and his team. “This makes it a suitable model for examining the infection of the intestine by Sars-CoV-2.”
In the experiment, the researchers infected intestinal organoids that had been kept under different culture conditions with Sars-CoV-2. Depending on the culture method, the intestinal cells had different densities of the ACE2 receptor on the cell surface. The infection tests showed that the coronavirus was able to persist and multiply in all organoids. Virus particles could be seen both outside and inside the intestinal cells under the electron microscope. The number of viruses increased dramatically over the course of 60 hours, as the scientists report. During this time, the infected cells increasingly began to produce immune-stimulating messenger substances such as cytokines and interferon. At the same time, the number of cells destroyed by the mechanism of apoptosis – the cellular suicide program – increased. “These observations provide clear evidence that Sars-CoV-2 can multiply in the cells of the gastrointestinal tract,” says Lamers ’colleague Bart Haagmans.
Hem cells of the intestinal mucosa are particularly susceptible
As the researchers found in more detailed analyzes, the virus in the intestine primarily affects the enterocytes, also called border cells. This cell type, with a dense border of brush-like extensions, lines the inside of the wall of the small intestine and is crucially involved in the absorption of nutrients and water from the porridge. The experiments revealed that Sars-CoV-2 can infect both the immature precursors of these mucosal cells and the mature enterocytes. Surprisingly, the level of infection was almost the same in all organoid variants – regardless of whether this cell initially had many or a few ACE2 receptors on its surface. “This indicates that apparently low densities of ACE2 receptors are sufficient for the viruses to enter these cells,” said Lamers and his colleagues.
According to the researchers, their results demonstrate that the coronavirus can attack the gut and how it does it. “However, we do not yet know whether the presence of Sars-CoV-2 in the gut of patients also plays a significant role in the transmission of the virus,” says Haagmans. “But our results suggest that you should take a very close look at this option.” For example, it might make sense to take smears from the anus instead of the throat in patients with diarrhea but without airway symptoms.
Source: Mart Lamers (Erasmus Medical Center, Rotterdam) et al., Science, doi: 10.1126 / science.abc1669