Altered intestinal ACE2 levels are associated with inflammation, severe disease and response to anti-cytokine therapy in IBD.

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.