Age, Inflammation, and Location of Active IBD May Boost SARS-CoV-2 Vulnerability

By Marilynn Larkin

May 20, 2020

NEW YORK (Reuters Health) - In patients with inflammatory bowel disease (IBD), age, inflammation and disease location are implicated in SARS-CoV-2 vulnerability, researchers suggest.

Dr. Jack Satsangi of the University of Oxford and colleagues found "intriguing differences" in the expression of angiotensin-converting enzyme 2 (ACE2) - the receptor for the SARS-CoV-2 spike protein - and transmembrane serine protease 2 (TMPRSS2), which primes the spike protein, in their analyses of samples from IBD patients and controls.

As reported in Gastroenterology, the team compared ACE2 and TMPRSS2 RNA expression in blood using paired-end sequencing and in ileal and in colonic mucosal biopsies (analyzing via microarray) from 138 treatment-naïve IBD patients and 154 controls with functional gastrointestinal disorders. Participants were recruited at six European centers from 2012-2015; none of them had been infected with SARS-CoV-2.

Among the findings:

- In controls, ACE2 expression in the terminal ileum was 25-fold higher than in the colon, consistent with previous studies;

- In IBD patients, ACE2 expression in the terminal ileum was increased 10-fold compared with the colon, whereas TMPRSS2 expression in the terminal ileum was lower than in the colon, both in controls and in IBD overall;

- Expression of ACE2 in inflamed Crohn's disease (CD) ileum was 60% lower than in controls, whereas ileal TMPRSS2 was 70% higher in non-inflamed CD tissue than in controls;

- Ileal ACE2 did not differ between ulcerative colitis (UC) patients and controls, but ileal TMPRSS2 was 30% higher;

- In CD, colonic ACE2 expression was increased by 30% relative to controls, while TMPRSS2 expression in the colon was similar between the two;

- In UC patients, the inflamed colonic mucosa expressed 70% more ACE2 transcript copies, and mucosal ACE2 was 50% higher in inflamed versus non-inflamed sites.

On multivariate analysis, ACE2 expression in the colon was associated with increasing age in controls, whereas in UC patients, it was influenced by inflammation at the biopsy site and disease severity.

In CD, colonic ACE2 expression was associated with the endoscopic inflammatory subscore. In addition, colonic TMPRSS2 expression was associated with high-sensitivity C-reactive protein and smoking status in controls, and with the Mayo subscore in UC.

Further, ACE2 expression in the ileum was lower in the few CD patients with stricturing (B2) and internal penetrating (B3) disease.

Summing up, Dr. Satsangi told Reuters Health by email, "ACE2 expression is increased in the IBD colon, both in CD and in UC; and is associated with alterations in endoscopic indices of severity as well as in circulating biomarkers of inflammation. Colonic TMPRSS2 levels also rise with hsCRP."

"In contrast, in ileal CD, ACE2 expression is reduced in the presence of active inflammation."

Taken together, "The data suggest that age, the presence of inflammation and anatomical location all may influence expression of ACE2 and TMPRSS2 in patients presenting with IBD," he concluded.

Epidemiological studies in IBD are underway to identify those most at risk, including those in the SECURE-IBD database (, he added. "Seroprevalence studies to identify the incidence of clinical and subclinical disease in these patients are in development."

Dr. Jordan Axelrad, a gastroenterologist at NYU Langone's Inflammatory Bowel Disease Center who was not involved in the study, told Reuters Health by email the findings "provide a mechanistic hypothesis associating active IBD with an increased risk of SARS-CoV-2 infection."

"The data are plausible," he said, "as active IBD and steroid exposure, often required for flares of disease, have been strongly linked with other viral infections, such as influenza, and suggest that uncontrolled inflammation is a greater risk factor for infection and associated complications than maintenance biologic or immunomodulator therapies."

"As patients in this study did not have COVID-19, additional research is required to validate that IBD patients with active colonic disease are indeed at a greater risk of SARS-CoV-2 infection and severe COVID-19 outcomes associated with enhanced ACE2 levels," Dr. Axelrad concluded.

SOURCE: Gastroenterology, online May 12, 2020.