From the outset of the COVID-19 pandemic, researchers have focused on the involvement of the respiratory system in the pathophysiology of the virus. A new study by Mount Sinai researcher Saurabh Mehandru, MD, suggests that the gastrointestinal tract may also play a key role in its replication.
The study looked at the expression of angiotensin-converting enzyme 2 (ACE2)—an enzyme that has been identified as a crucial receptor for the virus—and transmembrane protein, serine 2 (TMPRSS2) in the small intestines. “We know that the SARS-CoV-2 virus has a spike protein that tethers itself to ACE2 and that TMPRSS2 cleaves ACE2, enabling the virus to enter the host cell and replicate,” says Dr. Mehandru, Associate Professor of Medicine (Gastroenterology) at the Icahn School of Medicine at Mount Sinai. “Given that ACE2 regulates intestinal amino acid homeostasis, and the fact that COVID-19-positive patients are presenting with gastrointestinal symptoms such as diarrhea, nausea, and vomiting, we decided to look at the intersection between COVID-19, intestinal inflammation, and inflammatory bowel disease (IBD).”
Using endoscopic samples from patients he consented, and data from several large cohorts including the Mount Sinai Crohn’s and Colitis Registry (MSCCR), GSE 57945 series, GSE 100833 series, and GSE 73661 series, Dr. Mehandru found that the small bowel enterocyte brush border has the highest expression of ACE2 in the body and that the virus appears to be co-opting these physiological receptors to infect the small intestinal cells. The study, “Intestinal inflammation modulates the expression of ACE2 and TMPRSS2 and potentially overlaps with the pathogenesis of SARS-CoV-2-related disease,” was published September 24, 2020, in Gastroenterology.
“We cannot say if the infection came through the bloodstream or through the mouth,” Dr. Mehandru cautions. “We also do not know what the downstream consequences are, as in whether there is the potential for it to infect other parts of the body or other people. That said, the high expression of ACE2 receptors in the small intestine and the proportion of patients who have presented with gastrointestinal symptoms suggest gastrointestinal involvement in disease pathogenesis.”
“We do not know if intestinal infection contributes to worsening of the disease or if there are long-term implications in terms of patient survival, and that is one question we hope to answer."
Saurabh Mehandru, MD
Although ACE2 is also expressed in the respiratory system and the main cause of COVID-19-related mortality has been respiratory failure, the intestines also show robust expression of ACE2. “What we have shown is that this phenomenon is not occurring because there is a higher expression of ACE2 in the lungs but because the lungs bear the brunt of the damage from the virus,” he says.
Dr. Mehandru also explored the impacts of biologic and non-biologic IBD therapies on ACE2 and TMPRSS2 receptor expression. He found that infliximab was associated with significantly reduced ACE2 expression in inflamed colon samples and that ustekinumab increased ACE2 and TMPRSS2 expression in inflamed colon samples. Among non-biologics, corticosteroids, thiopurine, and 5-aminosalicylates were associated with reduced ACE2 expression in inflamed colon and rectum samples, but not in the ileum.
“There are regional differences occurring in the expression of ACE2 between the small and large bowel in the uninflamed state that also occur during inflammation, and treatment with IBD medications results in receptor expression returning to baseline levels,” Dr. Mehandru says. “Since inflammation seems to be driving receptor expression, patients should continue to receive IBD treatment when required.”
Ultimately, Dr. Mehandru suggests treating inflammation could result in better outcomes among patients with IBD not just because it prevents hospitalization that might expose them to COVID-19 infection but also because these immunosuppressive agents could prevent the overreaction of the immune system that researchers have linked to disease severity and mortality. But that potential protective factor requires further investigation, as does the impact of intestinal infection on the pathophysiology of the virus.
“We do not know if intestinal infection contributes to worsening of the disease or if there are long-term implications in terms of patient survival, and that is one question we hope to answer,” Dr. Mehandru says.
Saurabh Mehandru, MD
Associate Professor of Medicine (Gastroenterology)