Longitudinal multi-omic dynamics in hospitalized COVID-19 patients based on disease severity.

Despite a decline in global COVID-19 cases, severe disease requiring hospitalization remains a significant health burden. Microbial dysbiosis and microbial translocation have been implicated in COVID-19 severity through their contributions to systemic inflammation, yet the temporal dynamics of the microbiome and related metabolites across disease severity are not well defined. To address this, we conducted a longitudinal study of 22 hospitalized COVID-19 patients in Milan, Italy, classified as moderate, severe, or critical by the WHO criteria. Rectal and nasal microbiomes, plasma cytokines, bile acids, fatty acids, and gut barrier damage markers were measured at up to three timepoints over an average of 9 d. Critically ill patients exhibited sustained elevations in pro-inflammatory cytokines (IL-6, IL-8, and TNFα), increased gut barrier damage markers (LBP, zonulin, and sCD14), early depletion of beneficial commensals (including Faecalibacterium prausnitzii), and expansion of opportunistic pathogens such as Hungatella hathewayi and Erysipelatoclostridium ramosum. These microbial shifts were accompanied by the progressive loss of secondary and conjugated bile acids and increased levels of branched- and medium-chain fatty acids. Correlation analyses linked commensal taxa to reduced gut barrier damage and opportunistic pathogens to IL-6. Together, these findings define distinct trajectories associated with COVID-19 severity and highlight the importance of early interventions targeting microbial dysbiosis.