Mini-Gut Model Unlocks Secrets of COVID-19 Diarrhea

Researchers at Johns Hopkins Medicine claim to have identified multiple molecular pathways linked to diarrhea caused by COVID-19, offering possible therapeutic interventions utilizing human stem cells to create a sort of “mini intestine-in-a-dish.”

The findings from the experiments conducted in enteroids, a model of human intestinal tissue, are published in Cellular and Molecular Gastroenterology and Hepatology.

As a bonus, up to half of COVID-19 patients will also have diarrhea and unpleasant aches, fever, sore throat, cough, respiratory distress, and other symptoms that may accompany the virus. Thirty percent of them will go on to have long COVID, a chronic infection characterized by crippling symptoms like brain fog, chronic pain, shortness of breath, chest pain, and extreme fatigue.

While COVID-19 diarrhea is not life-threatening like cholera, it can often predict a severe case and also who gets the long COVID syndrome.”

Mark Donowitz, M.D., Emeritus Professor, Medicine and Physiology, School of Medicine, Johns Hopkins University

Certain aspects of COVID-19 diarrhea have been identified, such as the presence of the enzymes ACE2 (which the virus attaches to) and TMPRSS2 (which the virus uses to enter cells) in the intestine. The mechanisms were unclear up until now, but this research fills that knowledge gap by painting a more comprehensive picture of the mechanisms, which may point toward possible treatments.  

Donowitz and his colleagues employed enteroids, a model of the normal human gut, to try and figure out the mechanism by which COVID-19 diarrhea happened. Enteroids are single-layered cells in a petri dish that are oriented in the same direction as the normal intestine. They are created by encouraging human stem cells to differentiate into many of the intestinal lining cells.

The enteroids were exposed to a live SARS-CoV-2 virus, and the study team observed alterations in the expression and functionality of the gut cells' proteins.

Typically, diarrhea brought on by viruses, bacteria, or drug side effects results in modifications to the transport proteins that carry molecules across cell membranes. These modifications cause chloride secretion and block the absorption of sodium and chloride. Both effects happened in COVID-19 diarrhea, which is typical of diarrheal illnesses.

According to Donowitz, the chloride secretion in COVID-19 diarrhea was caused by a different class of proteins known as calcium-activated chloride channels, as opposed to many other diarrheal illnesses in which the protein at the core of cystic fibrosis is activated.

Unlike many diarrheal diseases, which are caused either by direct effects on the transport proteins or by the accompanying inflammation, Donowitz and his team observed a combination of the two in the enteroid cells, which made COVID-19 diarrhea unusual.

According to the research team, the inflammatory effects of COVID-19 in the lungs and other parts of the body may be comparable to the inflammation associated with COVID-19 diarrhea. This implies that treating COVID-19 diarrhea might involve investigating the function of inhibitors of this response.

The precise mechanisms of long COVID are a big mystery, although we now know that the virus can persist in the intestine for a long time. The next big question is to determine what exactly allows the virus to live in the intestine and what allows the virus to live over a long period.”

Mark Donowitz, M.D., Emeritus Professor, Medicine and Physiology, School of Medicine, Johns Hopkins University