Diabetes-associated lung physiology shapes Klebsiella pneumoniae infection dynamics

Type 2 diabetes mellitus (T2DM) is associated with increased susceptibility to bacterial pneumonia, yet the mechanisms by which diabetic host physiology influences pathogen establishment remain incompletely understood. Here, we investigated how diabetes-associated changes in the lung environment influence Klebsiella pneumoniae infection using leptin receptor-deficient (db/db) mice. Following acute lung infection, db/db mice exhibited increased bacterial burdens compared to nondiabetic controls, despite mounting a robust inflammatory cytokine response. Elevated pulmonary vascular endothelial growth factor concentrations were accompanied by alterations in the bronchoalveolar lavage fluid (BALF) metabolite profile, including enrichment of several amino acids and related metabolites. Consistent with increased nutrient availability, K. pneumoniae exhibited enhanced growth in BALF from db/db mice, and a glutamate-auxotrophic mutant demonstrated improved fitness during pulmonary infection. Using a barcoded K. pneumoniae library, we found that db/db mice supported significantly larger initial founding populations, leading to increased bacterial burden in the lungs. Increased founding populations were also observed in the liver and coincided with proportionally wider infection bottlenecks in the lung. Together, these findings demonstrate that diabetes-associated changes in lung physiology coincide with increased nutrient availability and reduced restrictions on bacterial establishment, highlighting bacterial founding population size as a distinct determinant of pneumonia susceptibility in T2DM.