Relevance of enriched expression of SARS-CoV-2 binding receptor ACE2 in gastrointestinal tissue with pathogenesis of digestive symptoms, diabetes-associated mortality, and disease recurrence in COVID-19 patients

Ashutosh Kumar; Muneeb A. Faiq; Vikas Pareek; Khursheed Raza; Ravi K. Narayan; Pranav Prasoon; Pavan Kumar; Maheswari Kulandhasamy; Chiman Kumari; Kamla Kant; Himanshu N. Singh; Rizwana Qadri; Sada N. Pandey; Santosh Kumar

the mucus cover lining GIT allowing their safe passage and even excretion in feces. 26 Mucus cells are abundant all along the length of the GIT which can contribute to the carriage and survival of SARS-CoV-2 thereby contributing to the so hypothesized fecal-oral transmission. This also hints that shedding of the virus in feces always may not be indicative of its replication in GI cells; all those patients who shed virus in stools don't necessarily present with digestive symptoms. 23 Healthy intestinal mucosa may not be well conducive for the entry of the virus due to the presence of unique multi-layer barrier system, though a prior inflammatory condition which disrupts mucosal barrier may render the lower GI entry of the SARS-CoV-2 using ACE2 receptor and its replication inside tissue plausible. 27 Inflammatory conditions in GIT enhance the expression of ACE2 in the luminal epithelium which can provide additional support for the entry of the virus. 28 Once inside the GI cells, the virus can replicate there and may orchestrate viral toxin mediated cell injury ensuing further inflammation, thereby, giving rise to gastroenteritis like symptoms (diarrhea, nausea, and vomiting, abdominal pain). 18, 20, 29 Other than the fecal-oral route, an alternative route of viral entry to the GI cells may be through the tissue microvasculature. Though this may not be highly probable but this premise does warrant consideration. In that case, fecal viral shedding can happen after sloughing of the inflamed/necrosed intestinal mucosa. Currently, data is limited which support presence of SARS-CoV-2 in the blood, however such evidence is available for other coronaviruses infections like SARS and MERS. 23, [30] [31] [32] ACE2 is known to regulate sodium-dependent amino acid and glucose transporters in the enterocytes brush border which physiologically engage in the absorption of nutrients from the digested food, and maintain osmotic and electrolyte balance across the GI lining epithelium. 9, 10 In a recent study Yan et al., 2020 showed that SARS-CoV-2 can bind to the complex of ACE2 with B0AT1(Slc6a19)-a major sodium dependent neutral amino acid transporter present in the epithelial lining of human intestine (and also in kidneys). 1, 33 The dysregulation of the intestinal ion transporters has been implicated in the pathophysiology of infectious diarrhea and malabsorption disorders. 11, 12 Literature also suggests that a dysregulation of these transporters can ensue interleukin/cytokine mediated intestinal inflammation and can give rise to digestive symptoms. 10 An enhanced GI expression of ACE2 is known in inflammatory bowel diseases (IBDs) which present with similar symptoms as in COVID-19 patients. 10, 34 Based on the findings of this study and supportive evidence from the literature, we propose that a virus binding-ACE2 mediated dysregulation of the sodium dependent nutrient transporters may be a plausible basis for the digestive symptoms in COVID-19. Prior intestinal inflammatory conditions like IBD may raise the susceptibility of SARS-CoV-2 infection through fecal-oral transmission. ACE2 mediated dysregulation of SGLT1 and/or SLC5A1 at intestinal epithelium also links it to the pathogenesis of diabetes mellitus. 14, 15 The SGLT1 transporters are physiologically involved in active absorption of glucose across the intestinal epithelium and its virus binding receptor ACE2 mediated dysregulation may exacerbate the existing impaired glycemic control in COVID-1