title: Metformin reduces airway glucose permeability and hyperglycaemia-induced Staphylococcus aureus load independently of effects on blood glucose.
abstract: 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.
  
  
  OBJECTIVE
  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 5×10(5) colony-forming units (CFU)/cm(2) 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 1×10(7) 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 hyperglycaemia-induced bacterial growth. Metformin might, therefore, be of additional benefit in the prevention and treatment of respiratory infection.
authors.affiliation: Division of Biomedical Sciences, Centre for Cell Physiology and Pharmacology, St George's, University of London, London, UK.
authors.forename: James P
authors.initials: JP
authors.lastname: Garnett
authors.forename: Emma H
authors.initials: EH
authors.lastname: Baker
authors.forename: Sonam
authors.initials: S
authors.lastname: Naik
authors.forename: Jodi A
authors.initials: JA
authors.lastname: Lindsay
authors.forename: Gwenan M
authors.initials: GM
authors.lastname: Knight
authors.forename: Simren
authors.initials: S
authors.lastname: Gill
authors.forename: John S
authors.initials: JS
authors.lastname: Tregoning
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Baines
mesh_terms: D000818:Animals; D058491:Bacterial Load / Q000187:drug effects*; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid; D002478:Cells, Cultured; D054370:Chemokine CXCL9 / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy; D053582:Interleukin-1alpha / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010539:Permeability / Q000187:drug effects; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000254:growth & development*; D054411:Receptors, Leptin / Q000172:deficiency / Q000235:genetics; D012137:Respiratory System / Q000378:metabolism / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D054370:Chemokine CXCL9; D053582:Interleukin-1alpha; D015850:Interleukin-6; D054411:Receptors, Leptin; D016212:Transforming Growth Factor beta; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D008687:Metformin
keywords: Airway Epithelium; Bacterial Infection; COPD Exacerbations; Respiratory Infection