Dysbiosis of gut microbiota in COVID-19 is associated with intestinal DNA phage dynamics of lysogenic and lytic infection

This study compared intestinal DNA phage dynamics and gut microbiota changes observed at the onset of coronavirus disease 2019 (COVID-19). The study participants included 19 healthy individuals and 19 patients with severe acute respiratory syndrome coronavirus 2 infection. Significant differences were observed in the diversity of the intestinal DNA virome after the onset of COVID-19 compared with that in healthy individuals. Classification by their tail morphology resulted in the order Caudovirales, a double-stranded DNA phage, accounting for >95% of all participants. In classifying phages based on host bacteria, a decreased number of phages infecting mainly the Clostridia class was observed immediately after the onset of COVID-19 and recovered over time. After the onset of COVID-19, two distinct movement patterns of intestinal phages and their host bacteria were observed: phage- and bacteria-predominant. The abundance of obligate anaerobes, such as <i>Clostridium_sense_strict_1</i>, <i>Fusicatenibacter</i>, and <i>Romboutsia</i>, and the phages hosting these bacteria decreased immediately after the onset of COVID-19, and faster phage recovery was observed compared with bacterial recovery. In contrast, the genus <i>Staphylococcus</i>, a facultative anaerobic bacterium, increased immediately after the onset of COVID-19, whereas the phages infecting <i>Staphylococcus</i> decreased. Furthermore, immediately after the onset of COVID-19, the percentage of lytic phages increased, whereas that of temperate phages decreased. These observations suggest that the gut microbiota dysbiosis observed immediately after the onset of COVID-19 may be linked to phage dynamics that control gut microbiota and may also affect the recovery from dysbiosis.IMPORTANCEBacteriophages infect and replicate with bacteria and archaea and are closely associated with intestinal bacteria. The symbiotic relationship between gut microbiota and bacteriophages is of interest, but it is challenging to study their dynamics in the human body over time. SARS-CoV-2 infection has been reported to alter the gut microbiota, which is involved in gut immune regulation and pathophysiology, although changes in the intestinal phages of patients with SARS-CoV-2 and their dynamic relationship with the gut microbiota remain unclear. SARS-CoV-2 infection, which follows a transient pathological course from disease onset to cure, may provide a reliable model to investigate these interactions in the gut environment. Therefore, this study aimed to elucidate the correlation between gut microbiota and intestinal DNA virome dynamics in COVID-19 pathogenesis. This study found that the dysbiosis observed in SARS-CoV-2 infection involves a growth strategy that depends on the phage or bacterial dominance.