Background Diabetes is a risk factor for respiratory
infection, and hyperglycaemia is associated with
increased glucose in airway surface liquid and risk of
Staphylococcus aureus infection.
Objectives To investigate whether elevation of
basolateral/blood glucose concentration promotes airway
Staphylococcus aureus growth and whether pretreatment
with the antidiabetic drug metformin affects this
relationship.
Methods Human airway epithelial cells grown at
air–liquid interface (±18 h pre-treatment, 30 μM–1 mM
metformin) were inoculated with 5×105 colony-forming
units (CFU)/cm2 S aureus 8325-4 or JE2 or
Pseudomonas aeruginosa PA01 on the apical surface
and incubated for 7 h. Wild-type C57BL/6 or db/db
(leptin receptor-deficient) mice, 6–10 weeks old, were
treated with intraperitoneal phosphate-buffered saline or
40 mg/kg metformin for 2 days before intranasal
inoculation with 1×107 CFU S aureus. Mice were culled
24 h after infection and bronchoalveolar lavage fluid
collected.
Results Apical S aureus growth increased with
basolateral glucose concentration in an in vitro airway
epithelia–bacteria co-culture model. S aureus reduced
transepithelial electrical resistance (RT) and increased
paracellular glucose flux. Metformin inhibited the
glucose-induced growth of S aureus, increased RT and
decreased glucose flux. Diabetic (db/db) mice infected
with S aureus exhibited a higher bacterial load in their
airways than control mice after 2 days and metformin
treatment reversed this effect. Metformin did not
decrease blood glucose but reduced paracellular flux
across ex vivo murine tracheas.
Conclusions Hyperglycaemia promotes respiratory
S aureus infection, and metformin modifies glucose flux
across the airway epithelium to limit hyperglycaemiainduced
bacterial growth. Metformin might, therefore, be
of additional benefit in the prevention and treatment of
respiratory infection.