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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 reduces Staphylococcus aureus-induced cytokine secretion. The concentration (pg/ml) of (A) GM-CSF; (B) IFNγ; (C) IL-1α, (D) IL-6, (E) MIG/CXCL9; (F) TGF-β was measured in the fluid (50 µl) covering the apical surface of H441 monolayers after 7 h in the absence and presence of apical S aureus,±metformin pretreatment, n=12. ****p<0.0001. GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; MIG, monokine induced by gamma interferon; TGF, transforming growth factor.
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THORAXJNL2012203178F5: Metformin reduces Staphylococcus aureus-induced cytokine secretion. The concentration (pg/ml) of (A) GM-CSF; (B) IFNγ; (C) IL-1α, (D) IL-6, (E) MIG/CXCL9; (F) TGF-β was measured in the fluid (50 µl) covering the apical surface of H441 monolayers after 7 h in the absence and presence of apical S aureus,±metformin pretreatment, n=12. ****p<0.0001. GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; MIG, monokine induced by gamma interferon; TGF, transforming growth factor.

Mentions: Granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon γ (INFγ), interleukins (IL-1α, IL-6), monokine induced by gamma interferon (MIG/CXCL9) and transforming growth factor β (TGFβ) concentrations were raised in the ASL of H441 monolayers after the addition of apical S aureus (p<0.0001; n=12; figure 5A–F). All except GM-CSF, were significantly reduced by metformin (p<0.0001; n=12). The concentration of basolateral glucose had no effect on cytokines produced in the presence or absence of S aureus or in the presence and absence of metformin (data not shown).


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 reduces Staphylococcus aureus-induced cytokine secretion. The concentration (pg/ml) of (A) GM-CSF; (B) IFNγ; (C) IL-1α, (D) IL-6, (E) MIG/CXCL9; (F) TGF-β was measured in the fluid (50 µl) covering the apical surface of H441 monolayers after 7 h in the absence and presence of apical S aureus,±metformin pretreatment, n=12. ****p<0.0001. GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; MIG, monokine induced by gamma interferon; TGF, transforming growth factor.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

THORAXJNL2012203178F5: Metformin reduces Staphylococcus aureus-induced cytokine secretion. The concentration (pg/ml) of (A) GM-CSF; (B) IFNγ; (C) IL-1α, (D) IL-6, (E) MIG/CXCL9; (F) TGF-β was measured in the fluid (50 µl) covering the apical surface of H441 monolayers after 7 h in the absence and presence of apical S aureus,±metformin pretreatment, n=12. ****p<0.0001. GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; MIG, monokine induced by gamma interferon; TGF, transforming growth factor.
Mentions: Granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon γ (INFγ), interleukins (IL-1α, IL-6), monokine induced by gamma interferon (MIG/CXCL9) and transforming growth factor β (TGFβ) concentrations were raised in the ASL of H441 monolayers after the addition of apical S aureus (p<0.0001; n=12; figure 5A–F). All except GM-CSF, were significantly reduced by metformin (p<0.0001; n=12). The concentration of basolateral glucose had no effect on cytokines produced in the presence or absence of S aureus or in the presence and absence of metformin (data not shown).

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