Abstract Rationale The elderly are susceptible to acute respiratory infections, which impose a substantial disease burden and high mortality. However, the role of the respiratory microbiome in these infections remains insufficiently understood, and the absence of an airway-specific bacterial genome catalog has further hindered its exploration. Given that the oral cavity serves as a major source of microbes colonizing the lower airways, simultaneous profiling of oral and airway microbiomes using metagenome-assembled genome (MAG) reconstruction enables comprehensive characterization of respiratory microbial diversity, including uncultured taxa. This study aims to establish a large-scale oral-airway bacterial genome collection and investigate its associations with respiratory infections in a longitudinal cohort of elderly adults. Methods This study integrated 12,616 publicly available human oral and airway metagenomic samples with 64,169 cultured bacterial genomes, together with newly sequenced samples from 933 elderly individuals to construct a high-quality bacterial genome database. The longitudinal elderly cohort enrolled 403 participants who had no history of acute respiratory infection in the preceding three months. Baseline sputum and oropharyngeal swab samples were collected upon enrollment for metagenomic sequencing. Participants were prospectively monitored for acute respiratory infections, with multiple samples collected during both the acute and recovery phases to capture temporal microbiome dynamics. Results Within this collection, we identified 99,215 high-quality, non-redundant strain-level genomes. Using optimized phylum-specific average nucleotide identity (ANI) thresholds to define species, these genomes were clustered into 2,474 species, of which 29.5% represented previously uncultured taxa. Leveraging this catalog to profile the respiratory microbiome of elderly participants, we stratified individuals according to whether they subsequently developed acute upper respiratory tract infections (URTIs). Enrichment of Neisseria species, including Neisseria subflava and other uncultured lineages, was observed in participants who developed URTIs. Longitudinal analysis of baseline samples compared with those collected 1, 7, and 30 days post-infection revealed a relative decline in the abundance of these Neisseria during the acute phase. Conclusions By constructing a comprehensive oral-airway bacterial genome database and establishing a longitudinal cohort of elderly adults, our study expands the repertoire of human respiratory microbiota, providing a valuable resource for understanding the relationship between the respiratory microbiome and infections in elderly individuals. We further identified Neisseria species, represented by Neisseria subflava, as potential microbial biomarkers predictive of future URTIs in this population. This abstract is funded by: National Key R&D Program of China
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