Intestinal Inflammation Modulates the Expression of ACE2 and TMPRSS2 and Potentially Overlaps With the Pathogenesis of SARS-CoV-2–related Disease

Suárez‐Fariñas, Mayte; Tokuyama, Minami; Wei, Guojian; Huang, Ruiqi; Livanos, Alexandra E.; Jha, Divya; Levescot, Anaïs; Irizar, Haritz; Kosoy, Roman; Cording, Sascha; Wang, Wenhui; Losic, Bojan; Ungaro, Ryan C.; Narzo, Antonio F Di; Martínez-Delgado, Gustavo; Suprun, Maria; Corley, Michael J.; Stojmirović, Aleksandar; Houten, Sander M.; Peters, Lauren; Curran, Mark; Brodmerkel, Carrie; Perrigoue, Jacqueline; Friedman, Joshua R.; Hao, Ke; Schadt, Eric E.; Zhu, Jun; Ko, Huaibin M.; Cho, Judy H.; Dubinsky, Marla; Sands, Bruce E.; Ndhlovu, Lishomwa C.; Cerf-Bensusan, Nadine; Kasarskis, Andrew; Colombel, Jean–Frédéric; Harpaz, Noam; Argmann, Carmen; Mehandru, Saurabh

doi:10.1053/j.gastro.2020.09.029

Cited by 102 publications

(104 citation statements)

References 61 publications

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“…SARS-CoV-2 infection did not induce any differences in intestinal-specific gene expression, or cellular phenotype. We also observed regional differences in the transcriptomic response to infection, with a more robust inflammatory signature in proximal HIOs as compared with colonic, which is of potential interest to clinicians caring for COVID-19 patients with pre-existing regionally specific GI diseases of increasing incidence and prevalence, such as Crohn, ulcerative colitis, or celiac ( Nowak et al., 2020 ; Suárez-Fariñas et al., 2021 ). We observed upregulation of apoptosis-related genes in both the infected colonic and proximal HIOs compared with mock-infected cells at 4 dpi, including three specific markers for necroptosis ( RIPK3 , RIPK1 , and MLKL ) in the colonic HIOs, indicating the induction of cell death ( Figure S4 A).…”

Section: Discussionmentioning

confidence: 74%

Human Pluripotent Stem Cell-Derived Intestinal Organoids Model SARS-CoV-2 Infection Revealing a Common Epithelial Inflammatory Response

Mithal¹,

Hume²,

Lindstrom-Vautrin³

et al. 2021

Stem Cell Reports

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leading to coronavirus disease 2019 (COVID-19) usually results in respiratory disease, but extrapulmonary manifestations are of major clinical interest. Intestinal symptoms of COVID-19 are present in a significant number of patients, and include nausea, diarrhea, and viral RNA shedding in feces. Human induced pluripotent stem cell-derived intestinal organoids (HIOs) represent an inexhaustible cellular resource that could serve as a valuable tool to study SARS-CoV-2 as well as other enteric viruses that infect the intestinal epithelium. Here, we report that SARS-CoV-2 productively infects both proximally and distally patterned HIOs, leading to the release of infectious viral particles while stimulating a robust transcriptomic response, including a significant upregulation of interferon-related genes that appeared to be conserved across multiple epithelial cell types. These findings illuminate a potential inflammatory epithelial-specific signature that may contribute to both the multisystemic nature of COVID-19 as well as its highly variable clinical presentation.

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Section: Discussionmentioning

confidence: 74%

Human Pluripotent Stem Cell-Derived Intestinal Organoids Model SARS-CoV-2 Infection Revealing a Common Epithelial Inflammatory Response

Mithal¹,

Hume²,

Lindstrom-Vautrin³

et al. 2021

Stem Cell Reports

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“…Network analyses highlighted hepatocyte nuclear factor 4α (HNF4A) as a key regulator of ileal ACE2 levels, whereas pro-inflammatory stimuli, such as cytokines, upregulate ACE2 in colonic organoids from patients with ulcerative colitis. Finally, another study did not observe an effect of both biologic and non-biological IBD medications (aminosalicylates, corticosteroids, thiopurines, TNF blockers) on ACE2 and TMPRSS2 receptor expression in uninflamed intestines 58 . Collectively, heterogeneous findings were obtained in studies on ACE2 mRNA expression levels in IBD, potentially owing to differences in patient cohorts, medical therapies or comorbidities.…”

Section: Covid-19 and Ibd Pathogenesismentioning

confidence: 87%

COVID-19: biologic and immunosuppressive therapy in gastroenterology and hepatology

Neurath

2021

Nat Rev Gastroenterol Hepatol

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The coronavirus disease 2019 (COVID-19) pandemic is an ongoing global health crisis causing major challenges for clinical care in patients with gastrointestinal diseases. Although triggering of anti-viral immune responses is essential for clearance of infection, some patients have severe lung inflammation and multiorgan failure due to marked immune cell dysregulation and cytokine storm syndrome. Importantly, the activation of cytotoxic follicular helper T cells and a reduction of regulatory T cells have a crucial, negative prognostic role. These findings lead to the question of whether immunosuppressive and biologic therapies for gastrointestinal diseases affect the incidence or prognosis of COVID-19 and, thus, whether they should be adjusted to prevent or affect the course of the disease. In this Review, data on the use of such therapies are discussed with a primary focus on inflammatory bowel disease, autoimmune hepatitis and liver transplantation. In particular, the roles of corticosteroids, classic immunosuppressive agents (such as thiopurines and mycophenolate mofetil), small molecules (such as Janus kinase (JAK) inhibitors), and biologic agents (such as tumour necrosis factor (TNF) blockers, vedolizumab and ustekinumab) are reviewed. Finally, the use of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines for the prevention of infection in patients with gastrointestinal diseases and concomitant immunosuppressive or biologic therapy will be discussed.

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“…We further performed a subgroup analysis of patients on anti-TNF and azathioprine therapy and came to the same conclusion that colonic ACE2 was decreased significantly in patients responding to anti-TNFα (endoscopic response, P = 0.0096; histologic response, P = 0.0039). In recent studies ( 14 , 32 ), international data from SECURE-IBD highlighted the association of corticosteroids with adverse COVID-19 outcomes and the probable safety of anti-TNF. The association between monotherapy or combination therapies and the risk of COVID-19 has been explored in some observational studies ( 14 , 32 , 42 ).…”

Section: Discussionmentioning

confidence: 99%

“…In recent studies ( 14 , 32 ), international data from SECURE-IBD highlighted the association of corticosteroids with adverse COVID-19 outcomes and the probable safety of anti-TNF. The association between monotherapy or combination therapies and the risk of COVID-19 has been explored in some observational studies ( 14 , 32 , 42 ). Our study used paired samples before and after anti-TNF therapy, which could minimize the inter-individual differences such as concomitant medication.…”

Section: Discussionmentioning

confidence: 99%

“…Similar immune signatures in IBD and COVID-19 indicate that medications of IBD may play a potential role in the treatment of COVID-19. Some studies supported that infliximab downregulated ACE2 expression in colon tissue of IBD ( 13 , 14 ). Another recent study has showed that biologics and steroids are linked to the significantly lower expression of ACE2 in intestinal lamina propria CD11b-enriched cells ( 15 ).…”

Section: Introductionmentioning

confidence: 96%

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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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Intestinal Inflammation Modulates the Expression of ACE2 and TMPRSS2 and Potentially Overlaps With the Pathogenesis of SARS-CoV-2–related Disease

Cited by 102 publications

References 61 publications

Human Pluripotent Stem Cell-Derived Intestinal Organoids Model SARS-CoV-2 Infection Revealing a Common Epithelial Inflammatory Response

Human Pluripotent Stem Cell-Derived Intestinal Organoids Model SARS-CoV-2 Infection Revealing a Common Epithelial Inflammatory Response

COVID-19: biologic and immunosuppressive therapy in gastroenterology and hepatology

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

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