LAUSR

Abstract The role of respiratory tract microbes and the relationship between respiratory tract and gut microbiomes in coronavirus disease 2019 (COVID‐19) remain uncertain. Here, the metagenomes of sputum and fecal samples from 66 patients with COVID‐19 at three stages of disease progression are sequenced. Respiratory tract, gut microbiome, and peripheral blood mononuclear cell (PBMC) samples are analyzed to compare the gut and respiratory tract microbiota of intensive care unit (ICU) and non‐ICU (nICU) patients and determine relationships between respiratory tract microbiome and immune response. In the respiratory tract, significantly fewer Streptococcus, Actinomyces, Atopobium, and Bacteroides are found in ICU than in nICU patients, while Enterococcus and Candida increase. In the gut, significantly fewer Bacteroides are found in ICU patients, while Enterococcus increases. Significant positive correlations exist between relative microbiota abundances in the respiratory tract and gut. Defensin‐related pathways in PBMCs are enhanced, and respiratory tract Streptococcus is reduced in patients with COVID‐19. A respiratory tract–gut microbiota model identifies respiratory tract Streptococcus and Atopobium as the most prominent biomarkers distinguishing between ICU and nICU patients. The findings provide insight into the respiratory tract and gut microbial dynamics during COVID‐19 progression, considering disease severity, potentially contributing to diagnosis, and treatment strategies.