Gut microbiota alterations in patients with persistent respiratory dysfunction three months after severe COVID-19

  1. Beate Vestad
  2. Thor Ueland
  3. Tøri Vigeland Lerum
  4. Tuva Børresdatter Dahl
  5. Kristian Holm
  6. Andreas Barratt-Due
  7. Trine Kåsine
  8. Anne Ma Dyrhol-Riise
  9. Birgitte Stiksrud
  10. Kristian Tonby
  11. Hedda Hoel
  12. Inge Christoffer Olsen
  13. Katerina Nezvalova Henriksen
  14. Anders Tveita
  15. Ravinea Manotheepan
  16. Mette Haugli
  17. Ragnhild Eiken
  18. Åse Berg
  19. Bente Halvorsen
  20. Tove Lekva
  21. Trine Ranheim
  22. Annika Elisabeth Michelsen
  23. Anders Benjamin Kildal
  24. Asgeir Johannessen
  25. Lars Thoresen
  26. Hilde Skudal
  27. Bård Reiakvam Kittang
  28. Roy Bjørkholt Olsen
  29. Carl Magnus Ystrøm
  30. Nina Vibeche Skei
  31. Raisa Hannula
  32. Saad Aballi
  33. Reidar Kvåle
  34. Ole Henning Skjønsberg
  35. Pål Aukrust
  36. Johannes Roksund Hov
  37. Marius Trøseid
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Abstract

Objective

Although COVID-19 is primarily a respiratory infection, mounting evidence suggests that the GI tract is involved in the disease, with gut barrier dysfunction and gut microbiota alterations being related to disease severity. Whether these alterations persist and could be related to long-term respiratory dysfunction is unknown.

Design

From the NOR-Solidarity trial (n=181), plasma was collected during hospital admission and after three months, and analyzed for markers of gut barrier dysfunction and inflammation. At the three-month follow-up, pulmonary function was assessed by measuring diffusing capacity of the lungs for carbon monoxide (DLCO), and rectal swabs for gut microbiota analyses were collected (n= 97) and analysed by sequencing of the 16S rRNA gene.

Results

Gut microbiota diversity was reduced in COVID-19 patients with persistent respiratory dysfunction, defined as DLCO below lower limit of normal three months after hospitalization. These patients also had an altered global gut microbiota composition, with reduced abundance of Erysipelotrichaceae UCG-003 and increased abundance of Flavonifractor and Veillonella, the latter potentially being linked to fibrosis. During hospitalization, increased plasma levels of lipopolysaccharide-binding protein (LBP) were strongly associated with respiratory failure, defined as pO2/fiO2-(P/F-ratio)<26.6 kPa. LBP levels remained elevated during and after hospitalization, and was associated with low-grade inflammation and persistent respiratory dysfunction after three months.

Conclusion

Persistent respiratory dysfunction after COVID-19 is associated with reduced biodiversity and gut microbiota alterations, along with persistently elevated LBP levels. Our results point to a potential gut-lung axis that should be further investigated in relation to long-term pulmonary dysfunction and long COVID.

Summary box

What is already known about this subject?

  • Mounting evidence suggests that the gastrointestinal tract is involved in the pathogenesis of COVID-19, with the putative SARS-CoV-2 receptor ACE 2 ubiquitously expressed in the gut.

  • In severe COVID-19, the gut-blood barrier is compromised, and leakage of microbial products, such as lipopolysaccharides (LPS), could affect the host’s response to COVID-19 infection.

  • COVID-19 patients exhibit an altered gut microbiota composition, which has been related to disease severity. However, it is currently not known whether dysbiosis or gut barrier dysfunction persist long-term after hospitalization, or whether microbiota-related mechanisms could be related to persistent pulmonary dysfunction.

What are the new findings?

  • COVID-19 patients with persistent respiratory dysfunction after three months had a lower microbial diversity and an altered gut microbiota composition at the same time point.

  • The microbiota alterations included reduced abundance of Erysipelotrichaceae UCG-003 and increased abundance of Veillonella and Flavonifractor.

  • During hospitalization, increased plasma levels of LBP were strongly associated with respiratory failure.

  • LBP levels remained elevated during and after hospitalization, and associated significantly with persistent respiratory dysfunction at three-month follow-up.

How might it impact on clinical practice in the foreseeable future?

Our findings point to a potential gut-lung axis in relation not only to respiratory failure during hospitalization, but also to long-term COVID-19 morbidity. Further studies on gut microbiota composition and gut barrier dysfunction as potential treatment targets and/or disease severity biomarkers in relation to long-term pulmonary dysfunction and long COVID are warranted.

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