Reduced expression of COVID-19 host receptor,ACE2is associated with small bowel inflammation, more severe disease, and response to anti-TNF therapy in Crohn’s disease

Abstract

Angiotensin-Converting Enzyme 2 (ACE2) has been identified as the host receptor for SARScoronavirus 2 (SARS-CoV-2) which has infected millions world-wide and likely caused hundreds of thousands of deaths. Utilizing transcriptomic data from four cohorts taken from Crohn's disease (CD) and non-inflammatory bowel disease (IBD) subjects, we observed evidence of increased ACE2 mRNA in ileum with demographic features that have been associated with poor outcomes in COVID-19 including age and raised BMI. ACE2 was downregulated in CD compared to controls in independent cohorts. Within CD, ACE2 expression was reduced in inflamed ileal tissue and also remarkably, from un-involved tissue in patients with a worse prognosis in both adult and pediatric cohorts. In active CD, small bowel ACE2 expression was restored by anti-TNF therapy particularly in anti-TNF responders. Collectively our data suggest that ACE2 downregulation is associated with inflammation and worse outcomes in CD. Methods Tissue Samples and Study SubjectsWe investigated association of ACE2 mRNA with age at collection, gender, smoking, BMI, diagnosis, CD sub-phenotypes and cytokine levels in 4 independent transcriptomic datasets of SB gene expression contingent on availability of meta-data for each cohort (see Table 1). Three of these cohorts have been described previously. In all 4 cohorts the small bowel specimens were taken from macroscopically normal appearing tissue.The 'SB139' [13] dataset was generated using whole Human Genome 4x44k Microarrays (Agilent) from formalin fixed paraffin embedded (FFPE) tissue taken from the unaffected margin of SB tissue resected during ileo-cecal or SB resection for complicated CD. Median age at time of surgery, which were all performed at Cedars-Sinai Medical Center, Los Angeles, was 32 years. The 'WashU' dataset [14] was generated by RNA-seq and similarly was generated from FFPE tissue from the unaffected proximal margin of resected CD tissues and also from FFPE from non-IBD control subjects. These subjects had a median age of 51 years at time of surgery which were all performed at the University of Washington, St Louis. The 'RISK' [15, 16] dataset was generated by RNA-seq from ileal biopsies taken from pediatric subjects in a CD inception cohort from multiple centers across North America (median age at time of biopsy 12 years). Being an inception cohort the age of diagnosis and age at specimen collection are the same. The CD subjects in RISK cohort were divided into two groups: those that had no small bowel/ileal disease (cCD) and those where the ileum was involved (iCD). The 'Cedars100' [17] dataset has not been previously published but similarly, utilized FFPE from un-involved proximal resection margins from complicated CD surgeries (performed at Cedars-Sinai Medical Center) and transcriptomics were generated by RNA-seq. All study subjects in SB139 and Cedars100 were CD; the WashU cohort consisted of CD and non-IBD controls and RISK cohort is a mix of CD, UC, and non-IBD controls.In addition we looked at the effect ...

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“…In IBD patients not using steroids, no significant change in ACE2 and TMPRSS2 gene expression was found in biopsy samples ( Monteleone, Franze, & Laudisi, 2020 ). In another study, reduced ACE2 expression in biopsy samples from patients with Crohn’s disease was associated with inflammation and worse outcomes ( Potdar et al, 2020 ). In 138 treatment naïve IBD patients, while ACE2 gene expression was decreased in the ileum, it was increased in colon samples ( Krzysztof et al, 2020 ).…”