1. Altered Intestinal ACE2 Levels Are Associated With Inflammation, Severe Disease, and Response to Anti-Cytokine Therapy in Inflammatory Bowel Disease.
- Author
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Potdar AA, Dube S, Naito T, Li K, Botwin G, Haritunians T, Li D, Casero D, Yang S, Bilsborough J, Perrigoue JG, Denson LA, Daly M, Targan SR, Fleshner P, Braun J, Kugathasan S, Stappenbeck TS, and McGovern DPB
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Angiotensin-Converting Enzyme 2 genetics, Anti-Inflammatory Agents adverse effects, COVID-19 enzymology, COVID-19 immunology, COVID-19 virology, Case-Control Studies, Child, Child, Preschool, Colitis, Ulcerative enzymology, Colitis, Ulcerative genetics, Colitis, Ulcerative immunology, Crohn Disease enzymology, Crohn Disease genetics, Crohn Disease immunology, Databases, Genetic, Female, Gene Expression Regulation, Enzymologic, Host-Pathogen Interactions, Humans, Intestines enzymology, Intestines immunology, Male, Middle Aged, North America, RNA, Messenger genetics, RNA, Messenger metabolism, Receptors, Virus metabolism, SARS-CoV-2 enzymology, SARS-CoV-2 immunology, Severity of Illness Index, Treatment Outcome, Tumor Necrosis Factor Inhibitors adverse effects, Tumor Necrosis Factor-alpha metabolism, Young Adult, Angiotensin-Converting Enzyme 2 metabolism, Anti-Inflammatory Agents therapeutic use, Colitis, Ulcerative drug therapy, Crohn Disease drug therapy, Intestines drug effects, Tumor Necrosis Factor Inhibitors therapeutic use, Tumor Necrosis Factor-alpha antagonists & inhibitors
- 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., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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