Scientists Uncover Why Some Respiratory Symptom-Free COVID-19 Patients Develop Gut Issues

Around one-third of people diagnosed with Covid-19, the disease caused by SARS-CoV-2, experience gastrointestinal issues yet many lack the respiratory symptoms most commonly associated with the coronavirus. Now, a team of researchers has determined that the virus can infect human intestinal cells where they can multiply and affect the gut.

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Because SARS-CoV-2 can be detected in stool samples, it has been suggested that the virus can be spread through fecal-oral transmission in addition to tiny droplets spread through coughing and sneezing. Key similarities exist between organs of the respiratory and intestinal systems, particularly their presence of angiotensin-converting enzyme 2 (ACE2) receptors, which allows coronaviruses to enter human cells. To determine whether intestinal cells can also become infected and facilitate reproduction of the cells, researchers from the Hubrecht Institute in Utrecht, Erasmus MC University Medical Center Rotterdam, and Maastricht University in the Netherlands created human intestinal organoids. Organoids are small 3D structures grown from adult stem cells in a lab setting used to replicate the functioning of larger organs and, in this case, were made from gut epithelial stem cells from the intestinal lining.

Intestinal organoids were cultured to contain varying levels of ACE2 receptors and were then injected with both SARS-CoV-2 and SARS-CoV, the coronavirus responsible for severe acute respiratory syndrome (SARS) that swept the globe in 2003. Regardless of the number of ACE2 receptors, both viruses rapidly infected the organoids and were observed multiplying over time both inside and outside of human cells. RNA sequencing further determined which genes were active in the intestinal cells and which reacted to the virus. Both coronaviruses resulted in similar infection rates and were confirmed in a second experiment, suggesting that the intestines may also be targeted by the viruses.

Intestinal organoids, the right one infected with coronavirus SARS-CoV-2. The coronavirus is colored white, the organoids themselves are colored blue and green. Joep Beumer/Hubrecht Institue​

“The observations made in this study provide definite proof that SARS-CoV-2 can multiply in cells of the gastrointestinal tract. However, we don't yet know whether SARS-CoV-2, present in the intestines of Covid-19 patients, plays a significant role in transmission,” said study author Bart Haagmans in a statement.

The researchers add that their findings serve as a new model for studying Covid-19 and could help to develop future treatments and find ways to block the entry of the virus into human cells. In addition to throat and nose swabs, doctors may also consider rectal swabs or stool samples to determine infection in patients without respiratory symptoms.

SARS-Cov-2 is the third pathogenic coronavirus to jump from animals to humans in the last 20 years, which the researchers say suggests “that novel zoonotic coronavirus spillovers are likely to occur in the future.” Understanding how coronaviruses infect humans and what cells they target is a crucial part of understanding, preventing, and treating infection during future outbreaks. The researchers will next work to pinpoint potential differences between infections in the lung and intestine by comparing organoids from each organ infected with SARS-CoV-2.

Intestinal organoid infected with coronavirus SARS-CoV-2. The coronavirus is colored white, the organoids themselves are colored blue and green. Joep Beumer/Hubrecht Institute​

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