Altered gut microbial metabolites could mediate the effects of risk factors in Covid-19

Abstract

Coronavirus disease 2019 (Covid-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is now pandemic. While most Covid-19 patients will experience mild symptoms, a small proportion will develop severe disease, which could be fatal. Clinically, Covid-19 patients manifest fever with dry cough, fatigue and dyspnoea, and in severe cases develop into acute respiratory distress syndrome (ARDS), sepsis and multi-organ failure. These severe patients are characterized by hyperinflammation with highly increased pro-inflammatory cytokines including IL-6, IL-17 and TNF-alpha as well as C-reactive protein, which are accompanied by decreased lymphocyte counts. Clinical evidence supports that gut microbiota dysregulation is common in Covid-19 and plays a key role in the pathogenesis of Covid-19. In this narrative review, we summarize the roles of intestinal dysbiosis in Covid-19 pathogenesis and posit that the associated mechanisms are being mediated by gut bacterial metabolites. Based on this premise, we propose possible clinical implications. Various risk factors could be causal for severe Covid-19, and these include advanced age, concomitant chronic disease, SARS-CoV-2 infection of enterocytes, use of antibiotics and psychological distress. Gut dysbiosis is associated with risk factors and severe Covid-19 due to decreased commensal microbial metabolites, which cause reduced anti-inflammatory mechanisms and chronic low-grade inflammation. The preconditioned immune dysregulation enables SARS-CoV-2 infection to progress to an uncontrolled hyperinflammatory response. Thus, a pre-existing gut microbiota that is diverse and abundant could be beneficial for the prevention of severe Covid-19, and supplementation with commensal microbial metabolites may facilitate and augment the treatment of severe Covid-19.

FIGURE 1

Viral entry, dissemination and damage to various organs. Severe acute respiratory syndrome coronavirus 2 virus initially infects respiratory system. If not controlled, it could enter the circulation system and subsequently infect various organs such as heart, liver, kidney, brain and intestines. The virus may also initially gain entry into the digestive system, and could disseminate to other organs. The damage to major organs can cause severe consequences such as acute respiratory distress syndrome, microvascular thrombosis, disseminated intravascular coagulation, acute heart failure, liver dysfunction, acute kidney injury/kidney failure, encephalitis/stroke and intestinal inflammation

FIGURE 2

Gut dysbiosis in coronavirus disease 2019 (Covid‐19). Various risk factors of Covid‐19 including elderly, chronic diseases, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) gut infection, use of antibiotics and stress can cause gut dysbiosis. Dysbiosis contributes to hyperinflammation by increased intestinal and systemic chronic inflammation and decreased anti‐inflammation mechanisms. These facilitate the form of hyperinflammation after SARS‐CoV‐2 infection, resulting in severe Covid‐19

FIGURE 3

Anti‐inflammatory effect of butyrate. Butyrate exerts anti‐inflammatory effect through multiple mechanisms. Butyrate can reduce dysbiosis‐caused gut leakage, thus block the translocation of lipopolysaccharides and microbes, inhibiting systemic inflammation. Butyrate also increases colonocytes to secrete antimicrobial peptides to reduce microbial infections. Butyrate can activate regulatory T‐cells, which subsequently inhibit T‐cell activation, reducing cytokine production. It can also increase goblet cells to secrete mucins to protect from microbial infections. Through inhibition of multiple pro‐inflammatory pathways, butyrate can reduce the cytokine production by immune cells under effects of stimuli

FIGURE 4

Interactions between gut dysbiosis and organs in coronavirus disease 2019. Gut dysbiosis affects multiple organs to form bidirectional gut–organs axes. Bile acids produced in the liver are secreted into gut, which are metabolized by gut bacteria and reabsorbed into the liver to form enterohepatic circulation. Other bacterial metabolites such as butyrate can also be absorbed into the liver. In gut dysbiosis, lipopolysaccharides and microbes are able to cross gut barrier to enter the liver. After processing in the liver, they enter to circulation system. In case of liver disease, there are also activated immune cells and cytokines. All these can be secret into the intestines and other organs. Chronic diseases in cardiovascular system, lung, brain and other organs could also produce and secrete immune cells and cytokine into circulation system