Progressive Post-Acute Gut Microbiome Disruption Following SARS-CoV-2 Infection in Mice

SARS-CoV-2 infection is increasingly recognized to produce long-lasting physiological disturbances that extend beyond the acute phase. The gut microbiome has emerged as a potential contributor to post-infection outcomes, yet the longitudinal progression of microbial disruption following infection remains poorly defined. Here, we used a mouse model of SARS-CoV-2 infection to characterize gut microbiome dynamics at 7 (late acute phase), 14 (early recovery), and 21 (post-COVID condition, PCC) days post-infection (dpi). Viral RNA was detected in the lungs through 21 dpi. Longitudinal microbiome profiling revealed a two-phase restructuring marked by early shifts in Bacillota and Bacteroidota abundance, followed by pronounced post-acute dysbiosis characterized by reduced diversity, expansion of Bacillota, and near-complete loss of Bacteroidota. Functional pathway predictions showed progressive metabolic remodeling, including disruptions in nucleotide turnover, fermentation, and vitamin-related pathways. Together, these findings demonstrate that SARS-CoV-2 infection drives progressive and sustained alterations in gut microbial composition and function after the transition from acute infection through recovery into PCC.