No evidence so far indicates that food or drinks can transmit the virus that causes COVID-19, but new research at Washington University School of Medicine in St. Louis suggests that people with problems in the upper gastrointestinal (GI) tract may be vulnerable to infection after swallowing the virus.
Studying tissue from patients with a common disorder called Barrett’s esophagus, the researchers found that although cells in a healthy esophagus cannot bind to the SARS-CoV-2 virus, esophageal cells from patients with Barrett’s have receptors for the virus, and those cells can bind to and become infected by the virus that causes COVID-19.
The study is published online Jan. 20 in the journal Gastroenterology.
“There is no evidence yet that people with Barrett’s esophagus have higher rates of COVID-19 or are at any greater risk, but part of the reason is because that hasn’t been studied,” said senior investigator Jason C. Mills, MD, Ph.D. “Now that we’ve connected these dots, it may be worthwhile to look and see whether people with Barrett’s have higher rates of infection.”
Part of the reason it’s been considered safe to eat and drink most foods during the pandemic is that they are unlikely to carry viral particles. And even if some viral particles are attached to food, stomach acid neutralizes the SARS-CoV-2 virus.
But when stomach acid backs up, people develop a disorder called gastric reflux that can cause long-term damage to the esophagus. In those with reflux disease, which affects about one in five people in the U.S., acid from the stomach backs up into the esophagus, causing heartburn and damaging the lining of the esophagus.
In addition, standard medical management for patients with Barrett’s esophagus is to suppress gastric acid secretions with drugs such as proton pump inhibitors. By reducing stomach acidity, those drugs may inadvertently make it possible for the virus to pass through the stomach and into the intestine, where even the normal, healthy cells carry receptors for SARS-CoV-2.
Many patients with COVID-19 – most of whom contract it by breathing in the viral particles—develop GI symptoms such as abdominal pain and diarrhea. The virus also has been found in the stool of COVID-19 patients.
But this new study demonstrates that under the right circumstances, the virus also may have an impact in the upper part of the GI tract. As a result, Mills – a professor of medicine, of developmental biology, and of pathology and immunology – and his team believe esophageal cells in Barrett’s patients are potential gateways for infection.
“You can imagine that if someone already has low levels of the virus in their respiratory tract, that individual could swallow some respiratory secretions, and the virus could infect cells in the esophagus to make them sicker that way,” said Ramon U. Jin, MD, Ph.D., the paper’s co-first author and a clinical fellow in the Division of Medical Oncology who studies Barrett’s esophagus because it is a major risk factor for cancer of the esophagus. The other co-first author, Jeffrey W. Brown, MD, Ph.D., is an instructor in medicine in the Division of Gastroenterology.
In this study, the researchers analyzed tissue from 30 patients with Barrett’s esophagus and found that cells in the tissue samples all had receptors for the SARS-CoV-2 virus, which normal esophagus cells lack. They built and cultured mini organs from those and other esophagus tissue samples.
Some of the sample organs were built with cells that came from healthy people while others came from patients with Barrett’s esophagus. The scientists built the mini esophaguses, called organoids, in a dish to learn how those model organs interacted with the SARS-CoV-2 virus.
The virus was able to bind to and infect mini organs built from tissue from people with Barrett’s esophagus. Moreover, the more the cells in a specific patient’s mini esophagus culture resembled intestine, the more the virus bound to and infected that culture.
“The worry would be that, particularly for Barrett’s patients, there even may be a susceptibility to infection from foods containing viral particles,” Mills said. “This study provides data to indicate that we need to take a closer look to investigate whether a substantial portion of the population may be susceptible to infection through what they swallow.”
As of August 2020, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected over 20 million people worldwide (World Health Organization). The new coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 is characterized by a broad range of symptoms, from respiratory to neurological and digestive problems (1, 2). Although a small fraction of patients develop highly lethal pneumonia, at least 20% of COVID-19 patients may display one or more gastrointestinal (GI) symptoms (1), such as diarrhea, vomiting, and abdominal pain (2, 3).
SARS-CoV-2 tissue tropism can be directly linked to the diverse clinical manifestations of COVID-19. The receptor used by the virus to enter the cells is the angiotensin-converting enzyme 2 (ACE2), which is found in several tissues, including the GI epithelial cells and liver cells (4, 5).
SARS-CoV-2 was detected in biopsies of several tissues, including esophagus, stomach, duodenum and rectum, and endoscopy of hospitalized patients revealed esophageal bleeding with erosions and ulcers (2, 6).
Higher levels of ACE2 in the tissues may explain in part some of the comorbidities associated with severe COVID-19.
Recently, we showed that ACE2 was highly expressed in the lungs of people with pulmonary arterial hypertension and chronic obstructive diseases (7). Since the expression of ACE2 changes under conditions of cell stress, elevated glucose levels and hypoxia (8, 9), other comorbidities related to the GI tract can be associated with different forms of COVID-19.
Here we suggest that gastroesophageal reflux disease (GERD) and Barrett’s esophagus (BE) may represent novel comorbidities associated with COVID-19. In the United States, it has been estimated that 5.6% of adults have BE, a disease where GERD damages the esophageal squamous mucosa (10).
Here we demonstrated that ACE2 is highly expressed in the esophagus of patients with BE and that the acid pH associated with this condition is a key inducer of ACE2 expression. Human primary monocytes cultured in reduced pH display increased expression of ACE2 and increased viral load upon SARS-CoV- 2 infection.
We also show that patients using proton pump inhibitors, which are recommended for GERD treatment, have a higher risk of developing severe COVID-19, observed by an increased risk of ICU admittance and death.
Discussion
Our findings suggest that acid pH increases SARS-CoV-2 infection by up-regulating the ACE2 receptor, and this may have clinical implications for patients with GERD or Barrett’s esophagus. No clear mechanism exists linking alterations in pH and ACE2 expression. Although evidence indicates that hypoxic conditions can increase the expression of ACE2 (8, 9), the expression of neither SIRT1 nor HIF1A seem to be associated with Barrett’s esophagus (Table S2). We found that known regulators of ACE2 – HNF1B (23) and FOXA2
(24) – were up-regulated in 6 out of 8 Barrett’s esophagus transcriptomic studies (Table S2), suggesting that they may be involved with the pH-induced ACE2 expression in Barrett’s esophagus.
Pulmonary damage, one of the main features of severe COVID-19, may lead to acute hypoxia and further respiratory acidosis. It is possible that the acidosis in the blood of some patients with severe COVID-19 (25) worsen the disease by increasing the levels of ACE2 and facilitating the entry of SARS-CoV-2 into human cells. Hypoxia itself may contribute to the regulation of ACE2 (9, 26). In addition, elevated levels of the enzyme lactate dehydrogenase (which converts lactate from pyruvate) has been associated with worse outcomes in patients with COVID-19 (27). The excess of lactate may directly alter the extracellular and intracellular pH which in turn can impact ACE2 expression. The extent to which acute systemic acidosis contributes to COVID-19 severity is poorly known and deserves further research.
The drug famotidine suppresses gastric acid production by blocking the histamine 2 receptor in the stomach. Recently, Freedberg et al (28) have shown that early treatment of patients tested positive for SARS-CoV-2 significantly improved clinical outcomes among the hospitalized patients. Although the authors hypothesized that famotidine may have antiviral effects, it is possible that pH itself can play an important role in regulating ACE2 expression and limiting SARS-CoV-2 infection in patients.
We showed here that the previous use of PPIs is associated with unfavorable outcomes, such as the time of hospitalization, ICU admittance, and death. To the best of our knowledge, none of these associations were previously reported. Almario et al. (29) recently described that individuals using PPIs had higher chances for testing positive for COVID-19 when compared to those not using PPIs. Their hypothesis is that PPIs might increase the risk for COVID-19 by undermining the gastric barrier to SARS-CoV-2 and reducing the microbial diversity in the gut (29). Rather, we believe that PPIs are important markers of hidden comorbidities that involve the damage caused by the excess stomach acid in GI tissues.
By going from disease (Barrett’s esophagus) to molecule (ACE2) to cells (in vitro experiments) and back to clinical findings (COVID-19 patients), we showed that pH may have a great influence on SARS-CoV-2 infection and COVID-19 severity. Additional studies should be performed to not only confirm the clinical findings on a larger scale but also to assess the molecular mechanism related to pH-induced ACE2 expression.
reference link : doi: https://doi.org/10.1101/2020.09.10.20179135
More information: Ramon U. Jin et al. Tropism of SARS-CoV-2 for Barrett’s Esophagus may Increase Susceptibility to Developing COVID-19, Gastroenterology (2021). DOI: 10.1053/j.gastro.2021.01.024
