Gut microbiota alterations in patients with persistent respiratory dysfunction three months after severe COVID-19
Authors: Vestad Beate , Ueland Thor , Lerum Tøri Vigeland , Børresdatter Dahl Tuva , Holm Kristian , Barratt-Due Andreas , Kåsine Trine , Dyrhol-Riise Anne Ma , Stiksrud Birgitte , Tonby Kristian , Hoel Hedda , Olsen Inge Christoffer , Henriksen Katerina Nezvalova , Tveita Anders , Manotheepan Ravinea , Haugli Mette , Eiken Ragnhild , Berg Åse , Halvorsen Bente , Lekva Tove , Ranheim Trine , Michelsen Annika Elisabeth , Kildal Anders Benjamin , Johannessen Asgeir , Thoresen Lars , Skudal Hilde , Kittang Bård Reiakvam , Bjørkholt Olsen Roy , Ystrøm Carl Magnus , Skei Nina Vibeche , Hannula Raisa , Aballi Saad , Kvåle Reidar , Skjønsberg Ole Henning , Aukrust Pål , Hov Johannes Roksund , Trøseid Marius 
Published: July 2021

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.