LAUSR

BACKGROUND AND AIMS The host receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) is highly expressed in small bowel (SB). Our aim was to identify factors influencing intestinal ACE2 expression in Crohn's disease (CD), ulcerative colitis (UC) and non-inflammatory bowel disease (non-IBD) controls. METHODS Using bulk RNA-seq or microarray transcriptomics from tissue samples (4 SB and 2 colonic cohorts; CD=495; UC=387; non-IBD=94), we analyzed the relationship of ACE2 with demographics, disease activity and prognosis. We examined the outcome of anti-TNF and anti-IL12/IL-23 treatment on SB and colonic ACE2 expression in three clinical trials. Univariate and multivariate regression models were fitted. RESULTS ACE2 levels were consistently reduced in SB CD and elevated in colonic UC, when compared to non-IBD controls. Elevated SB ACE2 was also associated with demographic features (age and elevated BMI) associated with poor COVID-19 outcomes. Within CD, SB ACE2 was reduced in patients subsequently developing complicated disease. Within UC, colonic ACE2 was elevated in active disease and in patients subsequently requiring anti-TNF rescue therapy. SB and colonic ACE2 expression in active CD and UC were restored by anti-cytokine therapy, most notably in responders. CONCLUSIONS Reduced SB, but elevated colonic ACE2 levels in IBD are associated with inflammation and severe disease but normalized following anti-cytokine therapy suggesting compartmentalization of ACE2-related biology in SB and colonic inflammation. The restoration of ACE2 expression with anti-cytokine therapy may be important in the context of SARS-CoV-2 infection and potentially explain reports of reduced morbidity from COVID-19 in IBD patients treated with anti-cytokines.