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Disrupted Gut Integrity, Other Gut
Factors, Tied to COVID-19 Severity
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CROI 2021, Conference on Retroviruses and Opportunistic Infections, March 6-10, 2021
Mark Mascolini
Markers of disrupted intestinal barrier integrity signaled more severe COVID-19, according to an analysis of 60 people with SARS-CoV-2 infection and 20 people negative for the COVID-19 virus [1]. The study also linked higher microbial translocation in the gut and intestinal dysfunction to more severe COVID-19. An unreviewed preprint describing these findings appears online [2].
"All diseases begin in the gut," Hippocrates counseled about 2400 years ago, noted Wistar Institute researchers who conducted this study. And their findings seemed to endorse that wisdom for a disease considered primarily a respiratory disorder, COVID-19. The Philadelphia-based Wistar team used the analogy of HIV, which both infects the gut and ignites systemic inflammation, setting up a treacherous feedback loop involving HIV infection, systemic inflammation, intestinal permeability, microbial translocation in the gut, and systemic microbial spillage. They asked whether a similar vicious cycle involving lung infection by SARS-CoV-2, pulmonary injury, systemic inflammation, intestinal permeability, and gut microbial translocation may be a major driver of COVID-19 severity.
The study involved 80 people tested for SARS-CoV-2. Twenty tested negative and became a control group. Of the 60 who tested positive, 20 who remained outpatients got classified as having mild COVID-19, 20 admitted to the hospital but not to the intensive care unit (ICU) had moderate disease, and 20 who went to the ICU had severe disease. The groups were age-matched and 50% female. Plasma from all participants got tested for microbial translocation markers and inflammation markers and underwent metabolomic, lipidomic, and glycomic analysis.
Levels of zonulin, the only known driver of intestinal tight junction permeability, proved significantly higher with severe COVID-19 than with mild disease or no COVID-19. The same proved true for moderate COVID-19 versus mild or no COVID-19. Zonulin concentrations were also significantly higher in people who died than in those who survived.
Markers of microbial translocation and inflammation registered higher readings in people with moderate or severe COVID-19 than in those with mild or no COVID-19. This proved true for (1) LPS-binding protein, a signal of bacterial translocation, which was also nearly significantly higher with severe than moderate disease (P = 0.06), (2) the monocyte/neutrophil inflammation maker soluble CD14, (3) the fungal translocation marker beta-glucan, which was also significantly higher with severe than moderate COVID-19 (P = 0.04), and (4) the neutrophil inflammation marker MPO.
The researchers also found strongly positive correlations between (1) the systemic inflammation marker IL-6 and the bacterial translocation marker LPS-binding protein (rho = 0.85) and (2) IL-6 and the fungal translocation marker beta-d-glucan (rho = 0.66). Compared with mild COVID-19 and no COVID-19, severe and moderate COVID-19 were associated with plasma metabolomic profiles that indicate disrupted gut function (variables included citrulline, succinic acid, and kynurenine/tryptophan ratio). Analyses of other markers linked severe COVID-19 to lipidome and glycome disruption consistent with gut dysfunction.
Together, the Wistar team proposed, these findings tied more severe COVID-19 to markers of (1) disrupted intestinal barrier integrity, (2) higher microbial translocation, and (3) intestinal dysfunction. But they cautioned that their findings "do not imply that microbial translocation is the primary trigger of severe COVID-19" because multiple pathophysiologic pathways probably intersect in this labyrinthine syndrome.
Still, the researchers stressed, "the robust literature indicating that disrupted intestinal barrier and microbial translocation fuel inflammation during respiratory diseases supports our hypothesis and is consistent with our findings." They hope their work unleashes other investigators on a search for biomarkers of long-term COVID-19 complications and informs work toward defining strategies that prevent this disease or mitigate its severity.
References
1. Giron LB, Dweep H, Yin X, et al. Severe COVID-19 is fueled by disrupted gut barrier integrity. CROI 2021, Conference on Retroviruses and Opportunistic Infections, March 6-10, 2021. Abstract 114.
2. Giron LB, Dweep H, Yin X, et al. Severe COVID-19 is fueled by disrupted gut barrier integrity. medRxiv. doi: https://doi.org/10.1101/2020.11.13.20231209.
https://www.medrxiv.org/content/10.1101/2020.11.13.20231209v1
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