Down-Regulation of Colonic ACE2 Expression in Patients With Inflammatory Bowel Disease Responding to Anti-TNF Therapy: Implications for COVID-19

Abstract

Background and Aims: Angiotensin-converting enzyme II (ACE2) is the key molecule for understanding the pathophysiology of COVID-19. The risk of COVID-19 and impact of immunosuppressive treatment on disease course in patients with inflammatory bowel disease (IBD) remain controversial. We aimed to determine the change of intestinal ACE2 expression before and after biologics treatment including anti-tumor necrosis factor α (anti-TNFα), anti-integrin, and anti-interleukin (IL)12/23 in IBD patients. Methods: We analyzed the ACE2 expression through the public database of paired intestinal biopsies from IBD patients before and after biologic therapy. Change of ACE2 RNA and protein expression were validated in two independent cohorts (Birmingham cohort and Guangzhou cohort). The correlation between ACE2 expression and disease activity was also analyzed. Results: Mining information from the GEO database showed that compared with healthy control, intestinal ACE2 expression was downregulated in ileum of CD patients, while upregulated in colon of both CD and UC patients. Colonic ACE2 RNA expression was decreased significantly in patients responding to anti-TNFα but not anti-integrin and anti-IL12/23, which was validated in the Birmingham cohort. Using the Guangzhou cohort including 53 patients matched by pre- and post-anti-TNFα therapy, colonic ACE2 protein expression was significantly downregulated after anti-TNFα treatment in responders (P < 0.001) rather than non-responders. Colonic ACE2 expression was significantly higher in patients with severe histologically active disease compared with those with moderate (P < 0.0001) and mild (P = 0.0002) histologically active disease. Conclusion: Intestinal inflammation influences the expression of intestinal ACE2 in IBD patients, with different alterations in the ileum and colon. Colonic ACE2 expression was downregulated after anti-TNFα therapy in IBD patients responding to treatment. This might provide new clues regarding the risk of SARS-CoV-2 infection and the potential benefit of sustaining anti-TNFα treatment in patients with IBD.

Keywords: ACE2; COVID-19; anti-TNFα; inflammatory bowel disease; intestine.

Figure 1

The relative ACE2 mRNA expression level of intestinal mucosal biopsy specimens before and after biologic therapy with anti-TNFα (infliximab/IFX, A,C; golimumab/GLM, B), vedolizumab/VDZ (D) or ustekinumab/UST (E) in patients with CD (A,E) or UC (B–D) from GEO data sets. (F) RT-qPCR data of the intestinal mucosal ACE2 expression in IBD responders before and after anti-TNFα therapy. In the matched comparison (A,C–F), lines between two samples represent the change in ACE2 expression before and after treatment for one patient. In the unpaired comparison (B), mean and range are shown in the scatterplot. There was not statistical difference between the IBD patients before and after therapy. ns, not significant; *P < 0.05; ***P < 0.001 (in patients after vs. before therapy). ^#P < 0.05; ^###P < 0.001 (in healthy controls vs. patients before therapy).

Figure 2

The relative ACE2 protein expression in intestinal mucosal biopsy specimens from patients with CD by Immunohistochemistry assays. The expression level was measured by percentage of positively stained cells. The sample sizes of each group are shown in Supplementary Table 1. (A) ACE2 expression before and after anti-TNFα treatment (matched comparison). (B) ACE2 expression among different disease activity groups defined by endoscopic and histological assessment. Median and interquartile range are shown in the scatterplot. (C) Spearman rank correlation analysis between ACE2 expression of colonic epithelial cells and endoscopic or histological disease activity. (D) Representative images (immunohistochemical staining for ACE2) of the colonic biopsy specimens before and after anti-TNFα treatment. (a–c) Biopsy before treatment. The histological score is 6. The percentage staining of ACE2 in colonic epithelial cells is 80%. (d–f) Biopsy after treatment. The histological score is 1. The percentage staining of ACE2 in colonic epithelial cells is 20%. All scale bars are 100 μm. ns, not significant; **P < 0.01; ***P < 0.001, ****P < 0.0001.