Dissecting the Role of the Human Microbiome in COVID-19 via Metagenome-assembled Genomes

Coronavirus disease 2019 (COVID-19), primarily a respiratory disease caused by infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is often accompanied by gastrointestinal symptoms. However, little is known about the relation between the human microbiome and COVID-19, largely due to the fact that most previous studies fail to provide high taxonomic resolution to identify microbes that likely interact with the SARS-CoV-2 infection. Here we applied de novo assembly and binning strategies to reconstruct metagenome-assembled genomes (MAGs) from the whole-metagenome shotgun sequencing data of 514 nasopharyngeal and fecal samples of patients with COVID-19 and controls in a total of six discovery cohorts (publicly available). We reconstructed a total of 11,584 medium-and high-quality microbial MAGs and obtained 5,403 non-redundant MAGs (nrMAGs) with strain-level resolution. Thanks to the high taxonomic resolution of nrMAGs, we found that a significant reduction of strain richness for many species in the gut microbiome of COVID-19 patients. The gut microbiome signatures can accurately distinguish COVID-19 cases from healthy controls and the generality of COVID-19 microbiome features in machine learning models can be validated across different cohorts. We then demonstrated the ability of nrMAGs to predict the date of negative RT-qPCR result of patients with COVID-19 (progression of COVID-19) and this prediction linked some opportunistic pathogens to the progression of COVID-19, including nrMAGs from Klebsiella quasivariicola, Klebsiella pneumoniae, and Escherichia coli. To further characterize the relation between the human gut microbiome and COVID-19, we applied the GMPT method to move beyond the standard association analysis. Using GMPT, we identified a set of nrMAGs with a putative causal role in the clinical manifestations of COVID-19 and revealed their functional pathways (i.e., pentose phosphate pathway) that potentially interact with SARS-CoV-2 infection. Moreover, we found that the abundance of pentose phosphate pathway (PENTOSE-P-PWY) in COVID-19 patients was significantly higher than that in Non-COVID-19 controls at the community level. Finally, we demonstrated that the main findings of our study can be largely validated in three independent cohorts (314 fecal samples in total, publicly available). The presented results highlight the importance of incorporating the human gut microbiome in our understanding of SARS-CoV-2 infection and disease progression. The genomic content of nrMAGs presented here has the potential to inform microbiome-based therapeutic developments for COVID-19 progression and post-COVID conditions.