Habitat environment is associated with the microbiota of the human terminal airway.

While environmental exposures are closely associated with the human microbiome, the microbial landscape of the terminal airways remains largely uncharacterized due to the ethical challenges of tissue sampling. To address this gap, we analyzed surgically resected idiopathic lung bullae (localized developmental anomalies surrounded by otherwise normal tissue) to establish a baseline microbiome atlas. We performed ultra-deep metagenomic sequencing on terminal airway tissues from 60 subjects residing in two climatically distinct Chinese cities: Zhuhai (a subtropical coastal region) and Yinchuan (an arid, high-altitude industrial area on the Qinghai-Tibet Plateau). Our analysis revealed that the high-altitude Yinchuan cohort exhibited significantly higher microbial loads and alpha diversity compared to the coastal Zhuhai cohort. Functionally, the Yinchuan microbiome was enriched in taxa associated with fatty acid beta-oxidation, alongside a markedly higher burden of virulence factors and antibiotic resistance genes. These compositional and functional differences may be associated with regional variation in climate, altitude, and local antibiotic usage patterns, whereas the Zhuhai cohort exhibited greater fungal diversity. Ultimately, this study provides the tissue-resolved microbial atlas of the human terminal respiratory tract and reveals substantial differences in microbial composition and function across distinct habitat environments. Furthermore, these findings suggest a potential association between environmental conditions and variation in resident microbiota, providing a basis for future investigations into how environmental change may influence respiratory microecology and human health.