Increased colonic expression of ACE2 associates with poor prognosis in Crohn’s disease

Toyonaga, Takahiko; Araba, Kenza C.; Kennedy, Meaghan M.; Keith, Benjamin P.; Wolber, Elisabeth A.; Beasley, Caroline; Steinbach, Erin C.; Schaner, Matthew R.; Jain, Animesh; Long, Millie D.; Barnes, Edward L.; Herfarth, Hans H.; Isaacs, Kim L.; Hansen, Jonathan J.; Kapadia, Muneera R.; Guillem, José Gaston; Gulati, Ajay S.; Sethupathy, Praveen; Furey, Terrence S.; Ehre, Camille; Sheikh, Shehzad Z.

The host receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small intestine. Our aim was to study colonic ACE2 expression in Crohn's disease (CD) and non-inflammatory bowel disease (non-IBD) controls. We hypothesized that the colonic expression levels of ACE2 impacts CD course. We examined the expression of colonic ACE2 in 67 adult CD and 14 NIBD control patients using RNA-seq and quantitative (q) RT-PCR. We validated ACE2 protein expression and localization in formalin-fixed, paraffin-embedded matched colon and ileal tissues using immunohistochemistry. The impact of increased ACE2 expression in CD for the risk of surgery was evaluated by a multivariate regression analysis and a Kaplan–Meier estimator. To provide critical support for the generality of our findings, we analyzed previously published RNA-seq data from two large independent cohorts of CD patients. Colonic ACE2 expression was significantly higher in a subset of adult CD patients which was defined as the ACE2-high CD subset. IHC in a sampling of ACE2-high CD patients confirmed high ACE2 protein expression in the colon and ileum compared to ACE2-low CD and NIBD patients. Notably, we found that ACE2-high CD patients are significantly more likely to undergo surgery within 5 years of CD diagnosis, and a Cox regression analysis found that high ACE2 levels is an independent risk factor for surgery (OR 2.17; 95% CI, 1.10–4.26; p = 0.025). Increased intestinal expression of ACE2 is associated with deteriorated clinical outcomes in CD patients. These data point to the need for molecular stratification that can impact CD disease-related outcomes.