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Metformin reduces airway glucose permeability and hyperglycaemia-induced Staphylococcus aureus load independently of effects on blood glucose.

Garnett JP, Baker EH, Naik S, Lindsay JA, Knight GM, Gill S, Tregoning JS, Baines DL - Thorax (2013)

Bottom Line: S aureus reduced transepithelial electrical resistance (RT) and increased paracellular glucose flux.Metformin did not decrease blood glucose but reduced paracellular flux across ex vivo murine tracheas.Metformin might, therefore, be of additional benefit in the prevention and treatment of respiratory infection.

View Article: PubMed Central - PubMed

Affiliation: Division of Biomedical Sciences, Centre for Cell Physiology and Pharmacology, St George's, University of London, London, UK.

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.

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 5×10(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.

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Related in: MedlinePlus

Metformin (MF) reduces airway Staphylococcus aureus numbers in hyperglycaemic mice, without lowering blood glucose. Leptin receptor deficient (db/db) mice were inoculated with 107 CFU of S aureus strain 8325-4 intranasally. Before infection mice were treated with 200 μl 40 mg/ml metformin or phosphate-buffered saline (PBS) intraperitoneally. (A) Comparison of bacterial CFU recovered from BAL fluid of untreated and metformin treated wild-type (WT) and db/db mice on day 1 after infection. (B) Blood glucose concentration on the day of infection. (C) Number of cells; (D) number of neutrophils; (E) interleukin 6 (IL-6) concentration in BAL fluid on day 1 after infection. Individual mice are shown as data points, the horizontal bars represent mean ± SEM of n=9–14 ± SEM (pooled experiments), **p<0.01, ***p<0.001. BAL, bronchoalveolar lavage.
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THORAXJNL2012203178F2: Metformin (MF) reduces airway Staphylococcus aureus numbers in hyperglycaemic mice, without lowering blood glucose. Leptin receptor deficient (db/db) mice were inoculated with 107 CFU of S aureus strain 8325-4 intranasally. Before infection mice were treated with 200 μl 40 mg/ml metformin or phosphate-buffered saline (PBS) intraperitoneally. (A) Comparison of bacterial CFU recovered from BAL fluid of untreated and metformin treated wild-type (WT) and db/db mice on day 1 after infection. (B) Blood glucose concentration on the day of infection. (C) Number of cells; (D) number of neutrophils; (E) interleukin 6 (IL-6) concentration in BAL fluid on day 1 after infection. Individual mice are shown as data points, the horizontal bars represent mean ± SEM of n=9–14 ± SEM (pooled experiments), **p<0.01, ***p<0.001. BAL, bronchoalveolar lavage.

Mentions: Metformin treatment significantly reduced bacterial load in the airways of db/db mice compared with PBS treatment (p<0.01; n=9; figure 2A), to levels similar to those seen in WT mice (p>0.05). Surprisingly, this reduction in airway S aureus numbers occurred despite metformin having no significant effect on blood glucose levels over this period of time (p>0.05; n=10; figure 2B). Metformin had no effect on S aureus load in WT mice (p>0.05; n=9; figure 2A). There was no difference in total cell (n=10, figure 2C) or neutrophil (n=9, figure 2D) recruitment to the airways or BAL IL-6 (n=14, figure 2E) concentration after infection, between metformin-treated and PBS-treated mice.


Metformin reduces airway glucose permeability and hyperglycaemia-induced Staphylococcus aureus load independently of effects on blood glucose.

Garnett JP, Baker EH, Naik S, Lindsay JA, Knight GM, Gill S, Tregoning JS, Baines DL - Thorax (2013)

Metformin (MF) reduces airway Staphylococcus aureus numbers in hyperglycaemic mice, without lowering blood glucose. Leptin receptor deficient (db/db) mice were inoculated with 107 CFU of S aureus strain 8325-4 intranasally. Before infection mice were treated with 200 μl 40 mg/ml metformin or phosphate-buffered saline (PBS) intraperitoneally. (A) Comparison of bacterial CFU recovered from BAL fluid of untreated and metformin treated wild-type (WT) and db/db mice on day 1 after infection. (B) Blood glucose concentration on the day of infection. (C) Number of cells; (D) number of neutrophils; (E) interleukin 6 (IL-6) concentration in BAL fluid on day 1 after infection. Individual mice are shown as data points, the horizontal bars represent mean ± SEM of n=9–14 ± SEM (pooled experiments), **p<0.01, ***p<0.001. BAL, bronchoalveolar lavage.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3756442&req=5

THORAXJNL2012203178F2: Metformin (MF) reduces airway Staphylococcus aureus numbers in hyperglycaemic mice, without lowering blood glucose. Leptin receptor deficient (db/db) mice were inoculated with 107 CFU of S aureus strain 8325-4 intranasally. Before infection mice were treated with 200 μl 40 mg/ml metformin or phosphate-buffered saline (PBS) intraperitoneally. (A) Comparison of bacterial CFU recovered from BAL fluid of untreated and metformin treated wild-type (WT) and db/db mice on day 1 after infection. (B) Blood glucose concentration on the day of infection. (C) Number of cells; (D) number of neutrophils; (E) interleukin 6 (IL-6) concentration in BAL fluid on day 1 after infection. Individual mice are shown as data points, the horizontal bars represent mean ± SEM of n=9–14 ± SEM (pooled experiments), **p<0.01, ***p<0.001. BAL, bronchoalveolar lavage.
Mentions: Metformin treatment significantly reduced bacterial load in the airways of db/db mice compared with PBS treatment (p<0.01; n=9; figure 2A), to levels similar to those seen in WT mice (p>0.05). Surprisingly, this reduction in airway S aureus numbers occurred despite metformin having no significant effect on blood glucose levels over this period of time (p>0.05; n=10; figure 2B). Metformin had no effect on S aureus load in WT mice (p>0.05; n=9; figure 2A). There was no difference in total cell (n=10, figure 2C) or neutrophil (n=9, figure 2D) recruitment to the airways or BAL IL-6 (n=14, figure 2E) concentration after infection, between metformin-treated and PBS-treated mice.

Bottom Line: S aureus reduced transepithelial electrical resistance (RT) and increased paracellular glucose flux.Metformin did not decrease blood glucose but reduced paracellular flux across ex vivo murine tracheas.Metformin might, therefore, be of additional benefit in the prevention and treatment of respiratory infection.

View Article: PubMed Central - PubMed

Affiliation: Division of Biomedical Sciences, Centre for Cell Physiology and Pharmacology, St George's, University of London, London, UK.

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.

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 5×10(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.

Show MeSH
Related in: MedlinePlus