Abstract
Diabetes is associated with increased frequency of hospitalization due to bacterial lung infection. We hypothesize that increased airway glucose caused by hyperglycaemia leads to increased bacterial loads. In critical care patients, we observed that respiratory tract bacterial colonisation is significantly more likely when blood glucose is high. We engineered mutants in genes affecting glucose uptake and metabolism (oprB, gltK, gtrS and glk) in Pseudomonas aeruginosa, strain PAO1. These mutants displayed attenuated growth in minimal medium supplemented with glucose as the sole carbon source. The effect of glucose on growth in vivo was tested using streptozocin-induced, hyperglycaemic mice, which have significantly greater airway glucose. Bacterial burden in hyperglycaemic animals was greater than control animals when infected with wild type but not mutant PAO1. Metformin pre-treatment of hyperglycaemic animals reduced both airway glucose and bacterial load. These data support airway glucose as a critical determinant of increased bacterial load during diabetes.
Highlights
Respectively, Glk is the glucokinase that catalyses the reaction of glucose to glucose-6-phosphate for entry into the Entner-Doudoroff pathway and GtrS, together with GltR, forms a two-component regulatory system
Colonisation of the respiratory tract with organisms among critical care patients is associated with high blood glucose. 1,148 admissions to two central London teaching hospital critical care units were identified during the study period (2013–2014); of these 664 had a random blood glucose electronically recorded on admission and were able to be evaluated
In this study we demonstrated a clinical association between high blood glucose and respiratory tract bacterial colonisation
Summary
Respectively, Glk is the glucokinase that catalyses the reaction of glucose to glucose-6-phosphate for entry into the Entner-Doudoroff pathway and GtrS, together with GltR, forms a two-component regulatory system. We generated P. aeruginosa mutants in the oprB, gltK, gtrS and glk genes and used these mutant strains in in vitro and in vivo models. The mutants had drastically reduced growth in minimal medium containing glucose as the sole carbon source, whereas they were unaltered when grown in rich medium. In order to explore the effect of elevated glucose with minimal effects on the immune response, we used streptozocin induced diabetes[16], instead of genetically obese mice (with mutations in leptin signalling), which have a complex phenotype and impaired immune responses[17]. We observed that streptozocin induced hyperglycaemia led to increased bacterial load in the airways when mice were infected with wild type PAO1 but not with the glucose uptake and metabolism mutants. We clearly established that increased glucose is a major factor in the increased bacterial infection in diabetes and informed and preventive measures should be taken with these patients
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