Intestinal Barrier Biomarker ZO1 and Endotoxin Are Increased in Blood of Patients With COVID-19-associated Pneumonia

Abstract

Background/Aim: The present study was undertaken to investigate (i) whether hospitalized patients with COVID-19 pneumonia present intestinal barrier dysfunction with consequent translocation of endotoxin into the systemic circulation and (ii) whether intestinal barrier biomarkers have any prognostic role in terms of progression to severe respiratory failure. Patients and Methods: In this prospective study, 22 patients with COVID-19-associated pneumonia and 19 patients with non-COVID-19-related community-acquired pneumonia (CAP group) were studied while 12 healthy persons comprised the control group. Blood samples were collected on admission and analysed for serum levels of endotoxin and zonula occludens-1 (ZO1). Clinical courses regarding progression to severe respiratory failure (SRF) requiring mechanical ventilation were recorded. Results: Patients with COVID-19-associated pneumonia and patients with CAP presented significantly higher serum endotoxin and ZO1 concentrations on admission as compared to healthy controls. There was no difference in endotoxin levels between patients with COVID-19-related pneumonia and patients with CAP. In patients with COVID-19-related pneumonia, serum endotoxin concentrations were positively correlated with C-reactive protein and ferritin values. There were no significant differences in serum endotoxin and ZO1 concentrations between patients with severe and not severe COVID-19-related pneumonia, nor between patients who developed SRF and those who did not Conclusion: Patients with COVID-19-related pneumonia present intestinal barrier dysfunction leading to systemic endotoxemia. Admission values of endotoxin and ZO1 do not have any prognostic role for progression to SRF.Although the vast majority of patients infected with SARS-CoV-2 will suffer from a mild respiratory illness, some patients develop severe complications, such as acute respiratory distress syndrome, renal and hepatic dysfunction, coagulopathy with thromboses and acute cardiac injury, increasing the risk of mortality (1). In these severely ill patients with multiple organ dysfunction syndrome, usually no infectious bacterial focus is identified and blood cultures are negative but the clinical picture is compatible with sepsis, supporting the concept of viral sepsis (2).The intestine plays a central role in the pathophysiological sequence of events that lead from sepsis to multiple organ dysfunction, being characterized as the 'motor' of sepsis (3). Enterocytes in the small intestine and colon express the angiotensin-converting enzyme 2 receptor and can therefore be infected by the SARS-CoV-2 virus (4). A multicenter study with 204 patients with COVID-19 from Hubei, China, showed that half of the patients experienced gastrointestinal symptoms and one-third had diarrhoea. In addition, SARS-CoV-2 RNA is commonly detected in faeces from patients with COVID-19, with a 3-fold increased risk of detection in those with diarrhoea (5). Previous studies have provided evidence for intestinal microbiota alterations, while endotoxe...

The Effect of Bacterial Infections, Probiotics and Zonulin on Intestinal Barrier Integrity

“…Assimakopoulos et al showed that SARS-CoV-2 pneumonia is associated with an increase in the concentration of endotoxins and ZO-1 in serum, which indicates a dysfunction of the intestinal barrier. Additionally, a positive correlation was found between the level of endotoxin and the concentration of CRP and ferritin [ 102 ]. Moreover, Prasad et al presented a relationship between COVID-19 and disturbances in the microbiota, and the tightness of the intestinal barrier.…”

The Rationale and Current Status of Endotoxin Adsorption in the Treatment of Septic Shock

“…Endotoxemia was also observed in 75% of 92 critically ill patients with COVID-19, with only two patients having positive blood cultures for Gram-negative organisms [90]. Significant endotoxemia was found in a cohort of 22 patients with COVID-19-related pneumonia, together with increased serum zonula occludens-1 levels, a marker of the integrity of the intestinal paracellular barrier, implying that there was intestinal barrier dysfunction and supporting the speculation that bacterial translocation from the gastrointestinal tract may complicate severe COVID-19 and may contribute to the cytokine storm [88,91]. In another study, the co-existence of low-grade endotoxemia with enhanced levels of zonulin in patients with COVID-19 was observed, as well as an association with thrombotic events [92].…”

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

“…In a recently published study, we have shown that patients with COVID-19-associated pneumonia have significantly higher serum ZO-1 concentrations as compared to healthy controls and this is associated with endotoxin translocation [ 44 ]. ZO-1 is a 210–225 kDa phosphoprotein that interacts with (i) the TJ proteins occludin, claudins and junctional adhesion molecule, (ii) molecular components of the intracellular tight junctional plaque such as ZO-2, ZO-3, afadin-6, cingulin and (iii) the actin cytoskeleton [ 9 ].…”