Mild and severe SARS-CoV-2 infection induces respiratory and intestinal microbiome changes in the K18-hACE2 transgenic mouse model

Abstract

Transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and declining economies around the world. K18-hACE2 mice develop disease resembling severe SARS-CoV-2 infection in a virus dose-dependent manner. The relationship between SARS-CoV-2 and the intestinal or respiratory microbiome is not fully understood. In this context, we characterized the cecal and lung microbiome of SARS-CoV-2 challenged K18-hACE2 transgenic mice in the presence or absence of treatment with the Mpro inhibitor GC376. Cecum microbiome showed decreased Shannon and Inv Simpson diversity index correlating with SARS-CoV-2 infection dosage and a difference of Bray-Curtis dissimilarity distances among control and infected mice. Bacterial phyla such as Firmicutes, particularly Lachnospiraceae and Oscillospiraceae, were significantly less abundant while Verrucomicrobiota, particularly the family Akkermansiaceae, were increasingly more prevalent during peak infection in mice challenged with a high virus dose. In contrast to the cecal microbiome, the lung microbiome showed similar microbial diversity among the control, low and high challenge virus groups, independent of antiviral treatment. Bacterial phyla in the lungs such as Bacteroidota decreased while Firmicutes and Proteobacteria were significantly enriched in mice challenged with a high dose of SARS-CoV-2. In summary, we identified changes in the cecal and lung microbiome of K18-hACE2 mice with severe clinical signs of SARS-CoV-2 infection.IMPORTANCEThe COVID-19 pandemic has resulted in millions of deaths. The host’s respiratory and intestinal microbiome can affect directly or indirectly the immune system during viral infections. We characterized the cecal and lung microbiome in a relevant mouse model challenged with a low and high dose of SARS-CoV-2 in the presence or absence of an antiviral Mpro inhibitor, GC376. Decreased microbial diversity and taxonomic abundances of the phyla Firmicutes, particularly Lachnospiraceae, correlating with infection dosage was observed in the cecum. In addition, microbes within the family Akkermansiaceae were increasingly more prevalent during peak infection, which is observed in other viral infections. The lung microbiome showed similar microbial diversity to the control, independent of antiviral treatment. Decreased Bacteroidota and increased Firmicutes and Proteobacteria were observed in the lungs in a virus dose-dependent manner. These studies add to a better understanding of the complexities associated with the intestinal microbiome during respiratory infections.

Gut microbiome dysbiosis in antibiotic-treated COVID-19 patients is associated with microbial translocation and bacteremia

“…Notably, a recent study reproduced these changes in the microbiome in an antibiotics-naïve cohort 7 , suggesting that the viral infection causes gut dysbiosis, either through gastrointestinal infection [61][62][63][64][65] or through a systemic inflammatory response 2,4 . 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.…”

“…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 cohort 7 , suggesting that the viral infection causes gut dysbiosis, either through gastrointestinal infection [61][62][63][64][65] or through a systemic inflammatory response 2,4 .…”

Gut microbiome dysbiosis during COVID-19 is associated with increased risk for bacteremia and microbial translocation

“…Notably, a recent study reproduced these changes in the microbiome in an antibiotics-naïve cohort 52 , suggesting that the viral infection causes gut dysbiosis, either through gastrointestinal infection [53][54][55][56][57] or through a systemic inflammatory response 2,4 . 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 49,58 . 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.…”

“…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 49–51 . Notably, a recent study reproduced these changes in the microbiome in an antibiotics-naïve cohort 52 , suggesting that the viral infection causes gut dysbiosis, either through gastrointestinal infection 53–57 or through a systemic inflammatory response 2, 4 .…”

Pathobiology and dysbiosis of the respiratory and intestinal microbiota in 14 months old Golden Syrian hamsters infected with SARS-CoV-2

“…We recently analyzed the lung and cecum microbiota of K18-hACE2 mice after a low and high dose SARS2 infection [32]. Within this animal model, we reported diversity and compositional changes in the respiratory and intestinal microbiota in a virus dose-dependent manner [32]. However, the artificial expression of hACE2 does not mirror the natural susceptibility observed in humans.…”