Environmental exposure augments the abundance and transferability of antibiotic resistance genes in the respiratory tract

Exposure to environmental pollutants has been linked to increased antibiotic resistance, a critical global health challenge. The respiratory microbiome constitutes a key reservoir of antibiotic resistance genes (ARGs). Here, we constructed a respiratory ARG catalog from sputum metagenomes of 1,128 individuals. We demonstrate that exposures, particularly to cigarette smoke and biofuels, are associated with increased abundance and enhanced mobility of respiratory ARGs. These resistome alterations correlate inversely with lung function, with elevated mobile ARG abundance detectable even in individuals with mild airflow limitation within normal spirometry. Specific ARGs, including opmD and tet(K), interact with smoking in relation to lung function impairment. Murine experiments recapitulate these findings, showing exposure-induced increases in homologous ARGs that confer heightened phenotypic resistance in cultured respiratory bacteria. Our results elucidate a pathway through which environmental pollutants augment the respiratory resistome, suggesting the need for actions to mitigate the antimicrobial resistance burden by addressing environmental pollution.