Increased colonic expression of ACE2 associates with poor prognosis in Crohn\u2019s disease

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

doi:10.1038/s41598-021-92979-2

Abstract

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.

Highlights

The host receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small intestine
We show that expression of ACE2, as well as TMPRSS2 and TMPRSS4, are highly variable in the intestines of adult and pediatric patients with Crohn’s disease (CD), and that their expression levels associate longitudinally with IBD outcome
We found that gene expression data from non-inflamed colon tissue from adult CD (N = 28) and non-IBD (NIBD) patients (N = 14) clearly segregate CD patients into two disease subtypes (Adult cohort 1)[15]

Summary

Introduction

The host receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small intestine. 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. Et al.[11] utilized bulk and single-cell transcriptomics and performed a global pathway analysis to identify ACE2-related gene regulatory networks Their analysis was not driven by clinical phenotypes, and their single cell RNA-sequencing data was derived only from ileum and not from the colon of CD patients. Our work reveals a novel connection between colonic ACE2 expression and CD-associated clinical outcomes These findings motivate future studies that focus on differences in ACE2 regulation between ileum and colon in Crohn’s disease and on whether colonic epithelial SARS-CoV-2 infectivity is greater in the ACE2-high subtype of IBD patients

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