Abstract
BackgroundRecent evidence demonstrated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) propagates in intestinal epithelial cells expressing Angiotensin-Converting Enzyme 2 (ACE2), implying that these cells represent an important entry site for the viral infection. Nicotinic receptors (nAChRs) have been put forward as potential regulators of inflammation and of ACE2 expression. As vagus nerve stimulation (VNS) activates nAChRs, we aimed to investigate whether VNS can be instrumental in affecting intestinal epithelial ACE2 expression.MethodsBy using publicly available datasets we qualified epithelial ACE2 expression in human intestine, and assessed gene co-expression of ACE2 and SARS-CoV-2 priming Transmembrane Serine Protease 2 (TMPRSS2) with nAChRs in intestinal epithelial cells. Next, we investigated mouse and human ACE2 expression in intestinal tissues after chronic VNS via implanted devices.ResultsWe show co-expression of ACE2 and TMPRSS2 with nAChRs and α7 nAChR in particular in intestinal stem cells, goblet cells, and enterocytes. However, VNS did not affect ACE2 expression in murine or human intestinal tissue, albeit in colitis setting.ConclusionsACE2 and TMPRSS2 are specifically expressed in epithelial cells of human intestine, and both are co-expressed with nAChRs. However, no evidence for regulation of ACE2 expression through VNS could be found. Hence, a therapeutic value of VNS with respect to SARS-CoV-2 infection risk through ACE2 receptor modulation in intestinal epithelia could not be established.
Highlights
Recent evidence demonstrated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) propagates in intestinal epithelial cells expressing Angiotensin-Converting Enzyme 2 (ACE2), implying that these cells represent an important entry site for the viral infection
Unsupervised clustering analysis identified 22 clusters (Fig. 2a), with clusters 8, 11, 13, 14, and 18 likely representing the epithelial cells based on their expression of E-cadherin (CDH1) and Villin-1 (VIL1) (Fig. 2b and c)
Both ACE2 and TMPRSS2 were expressed in the same clusters confirming specific gene expression in epithelial cells in ileum
Summary
Recent evidence demonstrated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) propagates in intestinal epithelial cells expressing Angiotensin-Converting Enzyme 2 (ACE2), implying that these cells represent an important entry site for the viral infection. Vagus nerve stimulation (VNS) has been put forward as potential therapy because of its ability to induce an anti-inflammatory effect through dampening systemic inflammatory responses. This ‘cholinergic anti-inflammatory pathway’ of the vagus nerve has been acknowledged for many years, in particular at the level (2020) 6:20 of sepsis-related cytokines Tumor Necrosis Factor (TNF), Interleukin (IL)-1, and High Mobility Group. Clear evidence supporting the value of VNS in treating COVID-19 is lacking
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