SARS CoV-2-Induced Viral Sepsis: The Role of Gut Barrier Dysfunction

Abstract

A considerable proportion of patients with severe COVID-19 meet Sepsis-3 criteria and share common pathophysiological mechanisms of multiorgan injury with bacterial sepsis, in absence of secondary bacterial infections, a process characterized as “viral sepsis”. The intestinal barrier exerts a central role in the pathophysiological sequence of events that lead from SARS-CoV-2 infection to severe systemic complications. Accumulating evidence suggests that SARS-CoV-2 disrupts the integrity of the biological, mechanical and immunological gut barrier. Specifically, microbiota diversity and beneficial bacteria population are reduced, concurrently with overgrowth of pathogenic bacteria (dysbiosis). Enterocytes’ tight junctions (TJs) are disrupted, and the apoptotic death of intestinal epithelial cells is increased leading to increased gut permeability. In addition, mucosal CD4(+) and CD8(+) T cells, Th17 cells, neutrophils, dendritic cells and macrophages are activated, and T-regulatory cells are decreased, thus promoting an overactivated immune response, which further injures the intestinal epithelium. This dysfunctional gut barrier in SARS-CoV-2 infection permits the escape of luminal bacteria, fungi and endotoxin to normally sterile extraintestinal sites and the systemic circulation. Pre-existing gut barrier dysfunction and endotoxemia in patients with comorbidities including cardiovascular disease, obesity, diabetes and immunosuppression predisposes to aggravated endotoxemia. Bacterial and endotoxin translocation promote the systemic inflammation and immune activation, which characterize the SARS-CoV-2 induced “viral sepsis” syndrome associated with multisystemic complications of severe COVID-19.

COVIDpro: Database for mining protein dysregulation in patients with COVID-19

“…The latter has been reported to bind to SARS-CoV-2 S protein 57 . LBP is known to increase in the presence of bacterial infections and is a marker of sepsis [58][59][60] COVID-19 patients this LBP increase is caused by dysfunction of the gut-blood barrier that leads to increased microbial translocation 61,62 .…”

Is compromised intestinal barrier integrity responsible for the poor prognosis in critically ill patients with pre-existing hyperglycemia?

“…In the present study, three intestinal barrier biomarkers (DAO, D-lactate, and LPS) were used to indicate the different parts of intestinal barrier injury, that DAO reflected the IECs damage [ 16 ], while D-lactate and LPS implied the compromised intestinal barrier integrity [ 17 ]. Under the severe pathophysiology challenges of critical illness, intestinal barrier injury accompanied with compromised intestinal barrier integrity commonly exists in critically ill patients, causing bacterial translocation, systemic inflammatory response, malabsorption, and consequently the poor prognosis [ 7 , 8 , 14 ]. Accordingly, intestinal barrier biomarkers can be used to predict the prognosis of critical illness [ 19 ], and D-lactate has been used in the prognosis of critically ill patients in Qiu’s study [ 20 ].…”

“…Previous studies have confirmed that gut dysbiosis is deeply associated with diabetes [ 27 ], and as the most specific symptom of diabetes, hyperglycemia has been proved to drive intestinal barrier dysfunction, impair intestinal barrier integrity, and cause bacterial translocation [ 12 ]. Nowadays, the cross-talks between diabetes, hyperglycemia, gut dysbiosis, intestinal barrier impairment, bacterial translocation, and systemic inflammatory response are gradually recognized [ 10 , 11 ] and the compromised intestinal barrier integrity and increased bacterial translocation in patients with pre-existing hyperglycemia have been considered to cause worse prognosis in COVID-19 [ 14 ].…”

“…Under the severe pathophysiology challenges of critical illness, intestinal barrier injury accompanied with compromised intestinal barrier integrity commonly exists in critically ill patients, causing bacterial translocation, systemic inflammatory response, malabsorption, and consequently the poor prognosis [7,8,14]. Accordingly, intestinal barrier biomarkers can be used to predict the prognosis of critical illness [19], and D-lactate has been used in the prognosis of critically ill patients in Qiu's study [20].…”

“…Our clinical study has found that the impairment of intestinal barrier got worse with the prolongation of hyperglycemia [ 13 ]. Recently, the compromised intestinal barrier integrity in COVID-19 has been well reviewed that predisposes patients with pre-existing hyperglycemia to aggravated endotoxemia and finally worse outcome [ 14 ]. Considering the co-result of critical illness and hyperglycemia, we assumed that the compromised intestinal barrier integrity might be responsible for the poor prognosis in critically ill patients with pre-existing hyperglycemia.…”