Analysis of the intestinal microbiota in COVID-19 patients and its correlation with the inflammatory factor IL-18

Abstract

The ongoing global pandemic of COVID-19 disease, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), mainly infect lung epithelial cells, and spread mainly through respiratory droplets. However, recent studies showed potential intestinal infection of SARS-CoV-2, implicated the possibility that the intestinal infection of SARS-CoV-2 may correlate with the dysbiosis of gut microbiota, as well as the severity of COVID-19 symptoms. Here, we investigated the alteration of the gut microbiota in COVID-19 patients, as well as analyzed the correlation between the altered microbes and the levels of intestinal inflammatory cytokine IL-18, which was reported to be elevated in the serum of in COVID-19 patients. Comparing with healthy controls or seasonal flu patients, the gut microbiota showed significantly reduced diversity, with increased opportunistic pathogens in COVID-19 patients. Also, IL-18 level was higher in the fecal samples of COVID-19 patients than in those of either healthy controls or seasonal flu patients. Moreover, the IL-18 levels were even higher in the fecal supernatants obtained from COVID-19 patients that tested positive for SARS-CoV-2 RNA than those that tested negative in fecal samples. These results indicate that changes in gut microbiota composition might contribute to SARS-CoV-2-induced production of inflammatory cytokines in the intestine and potentially also to the onset of a cytokine storm.

Potential intestinal infection and faecal–oral transmission of SARS-CoV-2

“…Interestingly, the level of another inflammatory cytokine mainly expressed in intestinal epithelial cells, IL-18 (refs 106 – 108 ), was found to increase upon fever onset and remain highly elevated in the acute phase of SARS-CoV infection in 88 patients 109 . Similarly, three studies respectively found that IL-18 levels were markedly increased in the serum 94 , 110 or faeces 65 of patients with COVID-19 and that increased levels of IL-18 were positively correlated with severe disease 94 . IL-18 maturation is induced by the activation of the intestinal inflammasome 106 , 108 , 111 .…”

“…Based on experimental and clinical evidence, neutralizing IL-18 by anti-IL-18 antibody or its natural inhibitor, soluble IL-18 binding protein (IL-18BP), can attenuate the inflammatory conditions 112 , 115 , 116 . Interestingly, IL-18 is elevated in patients with COVID-19 but not in patients with seasonal influenza 65 . Additionally, the IL-18 levels were higher in the faecal supernatants obtained from patients with COVID-19 who tested positive for SARS-CoV-2 RNA than in those faecal samples that tested negative, suggesting that IL-18 can potentially serve as an indicator for intestinal infection in COVID-19 (ref.…”

“…For example, a comparison of the proportion of gastrointestinal symptoms among patients with or without detectable virus in the intestine would be useful to understand the contribution of direct intestinal infection on the occurrence of gastrointestinal symptoms. Given that ACE2 has been shown to function in gut microbial ecology 64 and that alterations in the gut microbiota of patients with COVID-19 have been reported 65 , 66 , investigations are warranted to determine whether these alterations in gut microbiota are related to intestinal peristalsis and diarrhoea.…”

“…Additionally, the IL-18 levels were higher in the faecal supernatants obtained from patients with COVID-19 who tested positive for SARS-CoV-2 RNA than in those faecal samples that tested negative, suggesting that IL-18 can potentially serve as an indicator for intestinal infection in COVID-19 (ref. 65 ). We postulate that intestinal release of IL-18 during SARS-CoV-2 enteric infection might also be involved in CRS in COVID-19.…”

Could Perturbation of Gut Microbiota Possibly Exacerbate the Severity of COVID-19 via Cytokine Storm?

“…Studies have demonstrated alterations in the abundance and composition of fecal bacteria in COVID-19 patients compared to healthy controls. The pattern of the gut microbiota composition was found to be positively correlating with increased expression of IL-18, the proinflammatory cytokine ( 73 ).…”