Altered Intestinal ACE2 Levels Are Associated With Inflammation, Severe Disease, and Response to Anti-Cytokine Therapy in Inflammatory Bowel Disease

• Authors: Alka A Potdar, Cedars-Sinai Medical Center; Shishir Dube, Cedars-Sinai Medical Center; Takeo Naito, Cedars-Sinai Medical Center; Katherine Li, Janssen Research and Development, LLC; Gregory Botwin, Cedars-Sinai Medical Center; Talin Haritunians, Cedars-Sinai Medical Center; Dalin Li, Cedars-Sinai Medical Center; David Casero, Cedars-Sinai Medical Center; Shaohong Yang, Cedars-Sinai Medical Center; Janine Bilsborough, Cedars-Sinai Medical Center; Jacqueline G Perrigoue, Janssen Research and Development, LLC; Lee A Denson, University of Cincinnati; Mark Daly, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge; Stephan R Targan, Cedars-Sinai Medical Center; Phillip Fleshner, Cedars-Sinai Medical Center; Jonathan Braun, Cedars-Sinai Medical Center; Subra Cedars-Sinai Medical Center, Emory University; Thaddeus S Stappenbeck, Cleveland Clinic; Dermot PB McGovern, Cedars-Sinai Medical Center
• Journal Title: GASTROENTEROLOGY
• Volume: Volume 160, Number 3
• Publisher: W B SAUNDERS CO-ELSEVIER INC | 2021-02-06, Pages 809-+
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1053/j.gastro.2020.10.041
• Subjects: Health Sciences, Nutrition; Health Sciences, Immunology; Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Life Sciences & Biomedicine; Gastroenterology & Hepatology; Crohn's Disease; Ulcerative Colitis; Infliximab; Ustekinumab; MAINTENANCE THERAPY; CROHNS-DISEASE; SARS-COV; RECEPTOR; COLITIS; USTEKINUMAB; EXPRESSION; INDUCTION; CHILDREN

Abstract

Background And Aims: The host receptor for severe acute respiratory syndrome coronavirus 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 (IBD) controls. Methods: Using bulk RNA sequencing or microarray transcriptomics from tissue samples (4 SB and 2 colonic cohorts; n = 495; n = 387 UC; n = 94 non-IBD), we analyzed the relationship between ACE2 with demographics and disease activity and prognosis. We examined the outcome of anti–tumor necrosis factor and anti–interleukin-12/interleukin-23 treatment on SB and colonic ACE2 expression in 3 clinical trials. Univariate and multivariate regression models were fitted. Results: ACE2 levels were consistently reduced in SB CD and elevated in colonic UC compared with non-IBD controls. Elevated SB ACE2 was also associated with demographic features (age and elevated body mass index) associated with poor coronavirus disease 2019 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–tumor necrosis factor 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 after anti-cytokine therapy, suggesting compartmentalization of ACE2-related biology in SB and colonic inflammation. The restoration of ACE2 expression with anti-cytokine therapy might be important in the context of severe acute respiratory syndrome coronavirus 2 infection and potentially explain reports of reduced morbidity from coronavirus disease 2019 in IBD patients treated with anti-cytokines.