Why Does SARS-CoV-2 Invade the Gastrointestinal Epithelium?

Dear Editors:

In patients with coronavirus disease-29 (COVID-19), stool samples may persistently test positive, even when the respiratory sample is negative for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus. This phenomenon cannot be explained by the temporary gastrointestinal transit of swallowed saliva that contains the virus. Clues to solving this enigma were evident in a study performed by Xiao et al.¹ Gastrointestinal endoscopy was performed on patients who were diagnosed as positive for SARS-CoV-2 in stool samples, and biopsy samples were taken from the esophagus, gastric tissue, duodenum, and colon for histopathologic and immunofluorescent staining. The mucous epithelium of the esophagus, stomach, duodenum, and rectum showed no significant damage with hematoxylin and eosin staining; however, viral host receptor angiotensin-converting enzyme-2 and viral nucleocapsid protein–stained positive, mainly in the cytoplasm of gastrointestinal epithelial cells in the stomach, duodenum, and rectum. These results suggest that the SARS-CoV-2 virus may invade the mucosal cells of the stomach and the small and large intestines, multiply, and produce infectious virions.

There are 2 key findings in this study. The first is the surprising fact that coronaviruses are present in the highly acidic gastric epithelium—the spike protein of SARS-CoV-19 can mediate fusion with the host cell at a neutral pH. SARS-CoV-19 is completely inactivated by highly acidic conditions (pH 1–3) at 37°C, but moderate variations of pH conditions from 5 to 9 had little effect on virus titer, regardless of the temperature (from 4°C to 37°C).² In other words, for the SARS-CoV-2 virus to invade epithelial cells without being inactivated in the stomach, the gastric pH must be neutral.

The second important finding is that patients who tested positive on respiratory specimens but tested negative on the stool were, on average, 36 years old [(43 years × 73 cases – 49 years × 39 cases)/(73 – 39 cases) = 36 years]. The average age of the virus-positive population in stool samples was 49 years, suggesting that aging is involved in the ease of virus invasion. Age-related increases in gastric pH can be explained by atrophic gastritis (AG) and gastric intestinal metaplasia owing to Helicobacter pylori infection. In China and many other countries, the likelihood of having AG and intestinal metaplasia increases with age.³ In the stomachs of patients with intestinal metaplasia and/or AG, the pH of the surface of the gastric mucosa increase to ≥3,⁴ and for elderly AG, the pH found is 5–7.⁵ Based on these data, in the stomachs of elderly people with advanced chronic gastritis, it is presumed that the SARS-CoV-2 virus is not inactivated by stomach acid, but instead enters the epithelial cells of the stomach, and further invades the epithelial cells of the small and large intestines.

If this hypothesis is correct, an individual with a history of H pylori infection may be susceptible to fecal–oral infection. In the report from China, blood group A had a significantly higher risk for COVID-19 compared with non-A blood groups, whereas blood group O had a significantly lower risk for the infectious disease compared with non-O blood groups.⁶ According to >2000 case-control studies in Japan, blood group A is susceptible to H pylori infection and AG.⁷ Similarly, in Chinese case-control studies, the proportion of H pylori infection in blood group A individuals was significantly higher than that of non-A blood groups.⁸ These findings indicate that, for individuals with blood group A, the route of viral transmission is likely to include the risk of gastrointestinal infections, in addition to those of the respiratory tract. There are also concerns that users of drugs such as proton pump inhibitors or potassium-competitive acid blockers for treating gastroesophageal reflux disease—regardless of whether they have blood type A, chronic gastritis, or H pylori infection—may be similarly at risk.