COVID-19: Enzyme targeted by virus also influences gut inflammation

The multisite study, led by Cedars-Sinai and published today in the journal Gastroenterology, focused on angiotensin-converting enzyme 2 (ACE2), which normally plays a crucial health role by activating a hormone that helps regulate blood pressure. But in COVID-19 infections, the SARS-CoV-2 virus binds to ACE2 and uses it to invade and infect cells, "hijacking" them to spread the virus.

To learn more about how ACE2 affects the body, investigators examined its role in Crohn's disease and ulcerative colitis -- two types of IBD that can cause inflammation and scarring (fibrosis) in the digestive tract along with diarrhea, cramping and loss of appetite.

"We chose these disorders because COVID-19, while known for attacking the lungs, frequently causes gastrointestinal symptoms," said Dermot P. McGovern, MD, PhD, the Joshua L. and Lisa Z. Greer Chair in Inflammatory Bowel Disease Genetics and senior author of the new study. "It was important for us to understand how COVID-19 might affect IBD patients who are treated with anti-inflammatory medications. Also, there is increasing evidence that the GI tract may serve as an alternate route for uptake of SARS-COV-2 in general."

By examining records of nearly 1,000 patients at Cedars-Sinai, Washington University in St. Louis, Missouri, and multiple other centers across North America, the team found that levels of ACE2 in the small bowel were lower in Crohn's patients and higher in the colons of ulcerative colitis patients than they were in patients without IBD. The differing ACE2 levels were associated with poorer outcomes and more severe disease in the IBD patients.

"We saw that the effect of ACE2 depended on both its specific location in the gastrointestinal tract and the specific disease involved," said McGovern, professor of Medicine and Biomedical Sciences. "So, this enzyme was a double-edged sword."

In both types of IBD, treatment with infliximab, an anti-inflammatory drug, normalized the levels of ACE2 and was associated with improved disease outcomes in patients. This finding suggests these drugs, commonly used in autoimmune diseases, also might improve outcomes in COVID-19, the investigators said, "Overall, our study supports the potential paradoxical function of ACE2 in inflammation and COVID-19," McGovern explained. "Individuals with higher ACE2 expression may be at increased risk of infection with SARS-CoV-2. But judging from our discoveries of how ACE2 works in IBD, this enzyme likely has anti-inflammatory and anti-fibrotic functions that also could help certain COVID-19 patients recover from the virus."

Further research is needed to delineate the processes involving ACE2 and what they might mean for treating COVID-19 patients, he said. In support of that effort, the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health recently awarded a two-year grant of $677,036 to McGovern to examine overlaps in the mechanisms that drive inflammation in IBD and COVID-19.

The co-first authors of the new study were Alka A. Potdar, PhD, and Shishir Dube, PhD, from Cedars-Sinai. Other co-authors were from the University of Cincinnati; Cincinnati Children's Hospital Medical Center; Broad Institute of MIT and Harvard in Cambridge, Massachusetts; Harvard Medical School; Emory University School of Medicine in Atlanta; Children's Healthcare of Atlanta; the Cleveland Clinic; and Janssen Research and Development LLC, in Spring House, Pennsylvania.

Funding: Research reported in this publication was supported by internal funds from the F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute. The Cedars-Sinai MIRIAD IBD Biobank is supported by the F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under award numbers P01 DK046763 and U01 DK062413 and The Leona M and Harry B Helmsley Charitable Trust.

Disclosures: Cedars-Sinai has financial interests in Prometheus Biosciences Inc., a company which has access to the data and specimens in Cedars-Sinai's MIRIAD Biobank (including the data and specimens used in this study) and seeks to develop commercial products. Study co-authors Dermot P. McGovern, Janine Bilsborough and Stephan R. Targan own stock in Prometheus Biosciences Inc. Alka A. Potdar, Dalin Li, Bilsborough, Targan and McGovern are consultants for Prometheus Biosciences Inc. McGovern has consulted for Gilead, Pfizer, Boehringer Ingelheim, Qu Biologics and Bridge Biotherapeutics, and received grant support from Janssen. Thaddeus S. Stappenbeck has consulted for Janssen, Boehringer Ingelheim, Genentech and Takeda. Mark Daly is a founder of Maze Therapeutics. Lee A. Denson has received grant support from FrieslandCampina, Glycosyn and Janssen. Subra Kugathasan consults for Janssen, steering committee for DEVELOP registry and is Takeda DSMB chair. Katherine Li and Jacqueline G. Perrigoue are employees of Janssen Research and Development LLC.