Premises among SARS-CoV-2, dysbiosis and diarrhea: Walking through the ACE2/mTOR/autophagy route

Abstract

Recently, a new coronavirus (SARS-CoV-2) was discovered in China. Due to its high level of contagion, it has already reached most countries, quickly becoming a pandemic. Although the most common symptoms are related to breathing problems, SARS-CoV-2 infections also affect the gastrointestinal tract culminating in inflammation and diarrhea. However, the mechanisms related to these enteric manifestations are still not well understood. Evidence shows that the SARS-CoV-2 binds to the angiotensin-converting enzyme receptor 2 (ACE2) in host cells as a viral invasion mechanism and can infect the lungs and the gut. Other viruses have already been linked to intestinal symptoms through binding to ACE2. In turn, this medical hypothesis article conjectures that the ACE2 downregulation caused by the SARS-CoV-2 internalization could lead to decreased activation of the mechanistic target of mTOR with increased autophagy and lead to intestinal dysbiosis, resulting in diarrhea. Besides that, dysbiosis can directly affect the respiratory system through the lungs. Although there are clues to other viruses that modulate the ACE2/gut/lungs axis, including the participation of autophagy and dysbiosis in the development of gastrointestinal symptoms, there is still no evidence of the ACE2/mTOR/autophagy pathway in SARS-CoV-2 infections. Thus, we propose that the new coronavirus causes a change in the intestinal microbiota, which culminates in a diarrheal process through the ACE2/mTOR/autophagy pathway into enterocytes. Our assumption is supported by premises that unregulated intestinal microbiota increases the susceptibility to other diseases and extra-intestinal manifestations, which can even cause remote damage in lungs. These putative connections lead us to suggest and encourage future studies aiming at assessing the aforementioned hypothesis and regulating dysbiosis caused by SARS-CoV-2 infection, in order to confirm the decrease in lung injuries and the improvement in the prognosis of the disease.

SARS-CoV-2-Induced Gut Microbiome Dysbiosis: Implications for Colorectal Cancer

“…Although the most common COVID-19 symptoms are respiratory, SARS-CoV-2 infections also target the gastrointestinal tract, culminating in inflammation and intestinal cramps to diarrhea [ 52 ]. One hypothesis is that ACE2 downregulation, caused by SARS-CoV-2 infection, decreases activation of the mechanistic target of rapamycin (mTOR) and increases autophagy, leading to intestinal dysbiosis and diarrhea [ 52 ]. ACE2 expression in lungs is downregulated in wild-type mice infected with SARS-CoV and mice injected with recombinant SARS spike protein.…”

Autophagy, Unfolded Protein Response, and Neuropilin-1 Cross-Talk in SARS-CoV-2 Infection: What Can Be Learned from Other Coronaviruses

“…Although the most common symptoms are related to respiratory problems, ACE2 plays a central role in intestinal infection by SARS-CoV-2, which leads to gastrointestinal (GI) tract complications such as inflammation and diarrhea [ 175 ]. This is likely because of a putative ACE2 present in gut cells, which is involved in the uptake of amino acids such as tryptophan, leading to direct activation of mTOR in the presence of nutrients [ 176 ]. The mTOR also regulates the intestinal microbiota via affecting antimicrobial peptide expression in the Paneth cells of the small bowel.…”

“…The mTOR also regulates the intestinal microbiota via affecting antimicrobial peptide expression in the Paneth cells of the small bowel. Studies suggest that a tryptophan reduction followed by a partial or complete blockage of ACE2 by SARS-CoV-2, could cause a decrease in mTOR activation and intestinal dysbiosis, leading to intestinal inflammation and diarrhea [ 176 ]. This inflammation increases enterocytic intercellular spaces and intestinal permeability, allowing enhanced uptake of viral and bacterial antigens.…”

“…In addition, autophagy regulates Paneth cells by preventing the binding of microorganisms to the gut epithelial surface via ATG5, a required protein for autophagosome formation. Therefore, the autophagy process may interfere with gut microbiota through the ACE2/mTOR/autophagy pathway during COVID-19 infection, which leads to diarrhea [ 176 ].…”

A Dual-Route Perspective of SARS-CoV-2 Infection: Lung- vs. Gut-specific Effects of ACE-2 Deficiency

“…It has been suggested that SARS-CoV-2 gastrointestinal infection results in inflammation and diarrhea that affects up to 30% of cases (de Oliveira et al, 2020;Pan et al, 2020), and CT scans suggest that diarrhea may be linked to bowel wall abnormalities (Cardinale et al, 2020;Bhayana et al, 2020). Gut inflammation is supported by elevated fecal calprotectin (FC) in COVID19 patients with active or completed diarrhea (Effenberger et al, 2020).…”