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; Gaston Guillem, José; Koruda, Mark J.; Rahbar, Reza; Sadiq, Tim; Gulati, Ajay S.; Sethupathy, Praveen; Furey, Terrence S.; Ehre, Camille; Sheikh, Shehzad Z.

Background and Aims 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. Methods We examined the expression of colon ACE2 using RNA-seq and quantitative (q) RT-PCR from 69 adult CD and 14 NIBD control patients. In a subset of this cohort 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. Results Colonic ACE2 expression was significantly higher in a subset of adult CD patients (ACE2-high CD). 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 diagnosis, with a Cox regression analysis finding that high ACE2 levels is an independent risk factor (OR 2.18; 95%CI, 1.05-4.55; p=0.037). Conclusion Increased intestinal expression of ACE2 is associated with deteriorated clinical outcomes in CD patients. These data point to the need for molecular stratification that may impact CD disease-related outcomes.