Endotoxemia in patients with severe forms of COVID-19

COVID-19 patients typically present with fever and respiratory symptoms, but some patients also have gastrointestinal symptoms, such as diarrhea, vomiting and abdominal pain [1, 2]. The viral receptor angiotensin converting enzyme 2 (ACE2) was found to be highly expressed in gastrointestinal epithelial cells, suggesting that SARS-CoV-2 can directly infect and replicate in the gastrointestinal tract [3].

It has been suggested that pattern recognition receptors (PRRs) of the Toll-like receptor family, particularly TLR4, are involved in recognizing molecular patterns from SARS-CoV-2 to induce inflammatory responses [4]. TLR4 is commonly known to respond to pathogen-associated molecular patterns (PAMPs) of which the most potent is endotoxin, triggering inflammatory and innate immune responses. TLR4 can also be activated by damage-associated pattern molecules(DAMPs), such as HMGB1, released as a consequence of acute lung injury [5].

SARS-CoV-2 virus can generate various pathogenic host responses. Infected individuals may experience few or no symptoms at all, while others suffer from the direct effect of the virus on the lungs and an excessive immune response leading to a multi organ failure, analogous to what happens in sepsis. Furthermore, it has been hypothesized that endothelial injury and loss of gastrointestinal barrier function cause bacterial products, such as endotoxin,  to enter the circulation and contribute to the pathophysiology of COVID-19.

In a recent study of 19 patients with COVID-19 pneumonia, blood samples were analysed for endotoxin activity assay (EAA™), (1→3)-β-D-Glucan (BG), and 16S rRNA gene sequencing to determine the circulating bacteriome [6]. Serum BG is a marker of intestinal barrier dysfunction.

Of the 19 patients, 14 were in intensive care and 10 patients received mechanical ventilation. Eight patients (42%) had high EAA™ (≥ 0.6) and about half of the patients had high serum BG levels which tended to be higher in later in the illness. Although only 1 patient had a positive blood culture, 18 of 19 patients were positive for 16S rRNA gene amplification. Gram-negative bacteria were most abundant.

This observational study shows that endotoxemia as measured by the Endotoxin Activity and bacterial DNA are often found in the blood of patients with COVID-19 pneumonia, indicating that loss of intestinal barrier function significantly contributes to the pathogenesis of COVID-19.

The article is available here.


  1. Gu, J., B. Han, and J. Wang, COVID-19: Gastrointestinal Manifestations and Potential Fecal-Oral Transmission.Gastroenterology, 2020. 158(6): p. 1518-1519. (Pubmed)
  2. Lin, L., et al., Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection. Gut, 2020. 69(6): p. 997-1001. (Pubmed)
  3. Zhang, H., et al., The digestive system is a potential route of 2019-nCov infection: a bioinformatics analysis based on single-cell transcriptomes. bioRxiv, 2020: p. 2020.01.30.927806. (Link)
  4. Choudhury, A. and S. Mukherjee, In silico studies on the comparative characterization of the interactions of SARS-CoV-2 spike glycoprotein with ACE-2 receptor homologs and human TLRs. J Med Virol, 2020. (Pubmed)
  5. Andersson, U., W. Ottestad, and K.J. Tracey, Extracellular HMGB1: a therapeutic target in severe pulmonary inflammation including COVID-19? Mol Med, 2020. 26(1): p. 42. (Pubmed)
  6. Sirivongrangson, P., et al., Endotoxemia and circulating bacteriome in severe COVID-19 patients. medRxiv, 2020: p. 2020.05.29.20109785. (Link)