SARS-CoV-2 infection induces gut microbiome dysbiosis

A new study led by researchers from New York University Grossman School of Medicine – USA along with scientist from Yale University -USA has found that SARS-CoV-2 infections causes gut microbiome dysbiosis which in turn increases the risk for bacterial infections.

The study findings were published in the peer reviewed journal: Nature.
https://www.nature.com/articles/s41467-022-33395-6
 

Collectively, these results reveal an unappreciated link between SARS-CoV-2 infection, gut microbiome dysbiosis, and a severe complication of COVID-19, BSIs. The loss of diversity and immunosupportive Faecalibacterium in patients with BSIs mirrored a similar loss of diversity in the most severely sick mice deliberately infected with SARS-CoV-2, and as observed by other labs and other model systems 58,59,60.

Notably, a recent study reproduced these changes in the microbiome in an antibiotics-naïve cohort7, suggesting that the viral infection causes gut dysbiosis, either through gastrointestinal infection 61,62,63,64,65 or through a systemic inflammatory response2,4.

Furthermore, the pronounced increase in Akkermansiaceae in mice was also observed in our patient samples and has been reported previously in patients and in K18-hACE2 mice 58,66. However, the dysbiosis in patients with COVID-19 exceeded the microbiota shifts observed in the mouse experiments, including microbiome dominations by single taxa, which was not seen in the mouse experiments.

It is possible that in our experiment, mice were sacrificed before perturbations to the gut microbial populations reached a maximum. hACE2 knock-in mice, which display reduced disease 45, were not tested in the scope of this study but could provide additional insights in the future.

However, it is also plausible that the frequently administered antibiotic treatments that hospitalized COVID-19 patients receive exacerbated SARS-CoV-2-induced microbiome perturbations. Additionally, unlike the controlled environment experienced by laboratory mice, hospitalized patients are uniquely exposed to antimicrobial-resistant infectious agents present on surfaces and shed by other patients.

Despite these limitations of the mouse model, we observed that SARS-CoV-2 infection led to alteration of intestinal epithelial cells with established roles in intestinal homeostasis and gastrointestinal disease 67,68. Microbiome ecosystem shifts are likely both cause and consequence of these epithelial cell alterations since epithelial secretions are predicted to affect overall community structure disproportionately strongly 69,70.

For example, disruption of Paneth cell-derived antimicrobials including lysozyme are sufficient to impact microbiome composition 71,72,73, and, conversely, Akkermansia, which was increased in infected mice, can have epithelium remodeling properties 74.

Akkermansia has emerged as a genus of major interest, but its contributions to health or disease are still under research: beneficial health effects 53,75, as well as detrimental associations, have been reported76,77,78.

Our observation that the type of bacteria that entered the bloodstream was enriched in the associated stool samples is a well-characterized phenomenon in cancer patients 22,26,27, especially during chemotherapy-induced leukocytopenia when patients are severely immunocompromised 20,53.

COVID-19 patients are also immunocompromised and frequently incur lymphopenia, rendering them susceptible to secondary infections79. Our data suggest dynamics in COVID-19 patients may be similar to those observed in cancer patients: BSI-causing organisms may translocate from the gut into the blood, potentially due to loss of gut barrier integrity, through tissue damage downstream of antiviral immunity instead of chemotherapy.

Consistent with this possibility, soluble immune mediators such as TNFα and interferons produced during viral infections, including SARS-CoV-2, damage the intestinal epithelium to disrupt the gut barrier, especially when the inflammatory response is sustained as observed in patients with severe COVID-19 52,80,81.

Indeed, blood plasma in severely sick COVID-19 patients is enriched for markers of disrupted barrier integrity and higher levels of inflammation markers82, and nBSIs in these patients are often caused by gut microbial taxa 35, suggesting microbial translocation. Our data support this model with direct evidence because we were able to match sequencing reads from stool samples to genomes of species detected in the blood of patients.

We presented evidence that microorganisms from the dysbiotic gut microbiome translocate into the blood of COVID-19 patients, plausibly due to a combination of the immunocompromising effects of the viral infection and antibiotic-driven depletion of commensal gut microbes.

However, COVID-19 patients are also uniquely exposed to other potential factors predisposing them to bacteremia, including immunosuppressive drugs, long hospital stays, and catheters and our study is limited in its ability to investigate their individual effects.

Other limitations of our data include the few available whole genome sequences of blood isolates due to discarded blood cultures associated with several BSIs, and the temporal ordering of samples. Occasionally stool samples were collected after observation of BSI, and this mismatch in temporal ordering is counterintuitive for gut-to-blood translocation and a causal interpretation of our associations. However, the reverse direction, that blood infection populates and changes the gut community, is unlikely for the organisms identified in the blood, and if our associations were not causal, we would expect no match between BSI organisms and stool compositions.

Taken together, our findings support a scenario in which gut-to-blood translocation of microorganisms following microbiome dysbiosis leads to dangerous BSIs during COVID-19, a complication seen in other immunocompromised patients, including patients with cancer 22,26,27,83, acute respiratory distress syndrome84, and in ICU patients receiving probiotics85. We suggest that investigating the underlying mechanism behind our observations will inform the judicious application of antibiotics and immunosuppressives in patients with respiratory viral infections and increase our resilience to pandemics.