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The recent global emergence of the <i>SARS-CoV-2</i> pandemic has accelerated research in several areas of science whose valuable outputs and findings can help to address future health challenges in the event of emerging infectious agents. We conducted a comprehensive shotgun analysis targeting multiple aspects to compare differences in bacterial spectrum and viral presence through culture-independent RNA sequencing. We conducted a comparative analysis of the microbiome between healthy individuals and those with varying degrees of COVID-19 severity, including a total of 151 participants. Our findings revealed a noteworthy increase in microbial species diversity among patients with COVID-19, irrespective of disease severity. Specifically, our analysis revealed a significant difference in the abundance of bacterial phyla between healthy individuals and those infected with COVID-19. We found that <i>Actinobacteria</i>, among other bacterial <i>phyla</i>, showed a notably higher abundance in healthy individuals compared to infected individuals. Conversely, Bacteroides showed a lower abundance in the latter group. Infected people, regardless of severity and symptoms, have the same proportional representation of <i>Firmicutes</i>, <i>Proteobacteria</i>, <i>Actinobacteria</i>, <i>Bacteroidetes</i>, and <i>Fusobacteriales</i>. In addition to <i>SARS-CoV-2</i> and numerous phage groups, we identified sequences of clinically significant viruses such as <i>Human Herpes Virus 1</i>, <i>Human Mastadenovirus D</i>, and <i>Rhinovirus A</i> in several samples. Analyses were performed retrospectively, therefore, in the case of <i>SARS-CoV-2</i> various WHO variants such as <i>Alpha</i> (B.1.1.7), <i>Delta</i> (B.1.617.2), <i>Omicron</i> (B.1.1.529), and <i>20C</i> strains are represented. Additionally, the presence of specific virus strains has a certain effect on the distribution of individual microbial taxa.