Intestinal Receptor of SARS-CoV-2 in Inflamed IBD Tissue Seems Downregulated by HNF4A in Ileum and Upregulated by Interferon Regulating Factors in Colon

Verstockt, Bram; Verstockt, Sare; Rahiman, Saeed Abdu; Ke, Bo-Jun; Arnauts, Kaline; Cleynen, Isabelle; Sabino, J; Ferrante, Marc; Matteoli, Gianluca; Vermeire, Séverine

doi:10.1093/ecco-jcc/jjaa185

Cited by 41 publications

(47 citation statements)

References 64 publications

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“…The two recent landmark studies ( 6 , 7 ) have confirmed that SARS-CoV-2 could productively infect human gut enterocytes and intestinal organoids. In our study, we found that IBD patients had a higher expression of ACE2 in colon tissue while lower in ileum tissue vs. healthy control, which was consistent with the published data ( 13 ). Additionally, our result showed that the expression of colonic epithelial ACE2 was downregulated in IBD patients responding to anti-TNFα therapy, using GEO data analysis and then validated with qPCR and IHC assays.…”

Section: Discussionsupporting

confidence: 93%

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

Qiu

Jeffery

et al. 2021

Front. Med.

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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.

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Section: Discussionsupporting

confidence: 93%

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

Qiu

Jeffery

et al. 2021

Front. Med.

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“…25 Other studies involving human intestinal organoid experiments confirmed the mechanism of viral entry into intestinal cells, as well as the molecular expression pattern associated with the viral invasion in a context of intestinal inflammation (patients with inflammatory bowel diseases). 26,27 Differences in the expression of molecules related to viral entry depended on the analyzed intestinal segment, ileum or colon. 27 In the present study, the treatment with a mixture of acetate, propionate, and butyrate did not alter the viral load of intestinal biopsies or intestinal epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

Microbiota-derived short-chain fatty acids do not interfere with SARS-CoV-2 infection of human colonic samples

et al. 2021

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Microbiota-derived molecules called short-chain fatty acids (SCFAs) play a key role in the maintenance of the intestinal barrier and regulation of immune response during infectious conditions. Recent reports indicate that SARS-CoV-2 infection changes microbiota and SCFAs production. However, the relevance of this effect is unknown. In this study, we used human intestinal biopsies and intestinal epithelial cells to investigate the impact of SCFAs in the infection by SARS-CoV-2. SCFAs did not change the entry or replication of SARS-CoV-2 in intestinal cells. These metabolites had no effect on intestinal cells’ permeability and presented only minor effects on the production of anti-viral and inflammatory mediators. Together our findings indicate that the changes in microbiota composition of patients with COVID-19 and, particularly, of SCFAs do not interfere with the SARS-CoV-2 infection in the intestine.

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“…Interestingly, in contrast to worse outcomes in ACE2-high colon expressing adults, reduced ileal ACE2 expression in CD patients (N=50) in the Pediatric RISK Stratification cohort was significantly associated with colon and ileum disease involvement (p=0.0014), deeper ileal ulcers (p=0.0002), and macroscopic ileal inflammation (p=0.0156) compared to pediatric ileal ACE2-high (N=50) patients. These regional differences in ACE2 expression suggest that active intestinal inflammation alters ACE2 expression, with opposing regulation in ileum and colon 17, 18 . There are several points that must be noted with regard to future comparison of our findings with other studies.…”

Section: Discussionmentioning

confidence: 99%

Increased Colonic Expression of ACE2 Associates with Poor Prognosis in Crohn’s disease

Toyonaga

Araba

Kennedy

et al. 2020

Preprint

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Background and AimsThe host receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small intestine. Our aim was to study colonic ACE2 expression in Crohn’s disease (CD) and non-inflammatory bowel disease (non-IBD) controls. We hypothesized that the colonic expression levels of ACE2 impacts CD course.MethodsWe examined the expression of colon ACE2 using RNA-seq and quantitative (q) RT-PCR from 69 adult CD and 14 NIBD control patients. In a subset of this cohort we validated ACE2 protein expression and localization in formalin-fixed, paraffin-embedded matched colon and ileal tissues using immunohistochemistry. The impact of increased ACE2 expression in CD for the risk of surgery was evaluated by a multivariate regression analysis and a Kaplan-Meier estimator. To provide critical support for the generality of our findings, we analyzed previously published RNA-seq data from two large independent cohorts of CD patients.ResultsColonic ACE2 expression was significantly higher in a subset of adult CD patients (ACE2-high CD). IHC in a sampling of ACE2-high CD patients confirmed high ACE2 protein expression in the colon and ileum compared to ACE2-low CD and NIBD patients. Notably, we found that ACE2-high CD patients are significantly more likely to undergo surgery within 5 years of diagnosis, with a Cox regression analysis finding that high ACE2 levels is an independent risk factor (OR 2.18; 95%CI, 1.05-4.55; p=0.037).ConclusionIncreased intestinal expression of ACE2 is associated with deteriorated clinical outcomes in CD patients. These data point to the need for molecular stratification that may impact CD disease-related outcomes.

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Intestinal Receptor of SARS-CoV-2 in Inflamed IBD Tissue Seems Downregulated by HNF4A in Ileum and Upregulated by Interferon Regulating Factors in Colon

Cited by 41 publications

References 64 publications

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

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

Microbiota-derived short-chain fatty acids do not interfere with SARS-CoV-2 infection of human colonic samples

Increased Colonic Expression of ACE2 Associates with Poor Prognosis in Crohn’s disease

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