title: Metformin prevents the effects of Pseudomonas aeruginosa on airway epithelial tight junctions and restricts hyperglycaemia-induced bacterial growth.
abstract: Lung disease and elevation of blood glucose are associated with increased glucose concentration in the airway surface liquid (ASL). Raised ASL glucose is associated with increased susceptibility to infection by respiratory pathogens including Staphylococcus aureus and Pseudomonas aeruginosa. We have previously shown that the anti-diabetes drug, metformin, reduces glucose-induced S. aureus growth across in vitro airway epithelial cultures. The aim of this study was to investigate whether metformin has the potential to reduce glucose-induced P. aeruginosa infections across airway epithelial (Calu-3) cultures by limiting glucose permeability. We also explored the effect of P. aeruginosa and metformin on airway epithelial barrier function by investigating changes in tight junction protein abundance. Apical P. aeruginosa growth increased with basolateral glucose concentration, reduced transepithelial electrical resistance (TEER) and increased paracellular glucose flux. Metformin pre-treatment of the epithelium inhibited the glucose-induced growth of P. aeruginosa, increased TEER and decreased glucose flux. Similar effects on bacterial growth and TEER were observed with the AMP activated protein kinase agonist, 5-aminoimidazole-4-carboxamide ribonucleotide. Interestingly, metformin was able to prevent the P. aeruginosa-induced reduction in the abundance of tight junction proteins, claudin-1 and occludin. Our study highlights the potential of metformin to reduce hyperglycaemia-induced P. aeruginosa growth through airway epithelial tight junction modulation, and that claudin-1 and occludin could be important targets to regulate glucose permeability across airway epithelia and supress bacterial growth. Further investigation into the mechanisms regulating metformin and P. aeruginosa action on airway epithelial tight junctions could yield new therapeutic targets to prevent/suppress hyperglycaemia-induced respiratory infections, avoiding the use of antibiotics.
authors.affiliation: Institute for Infection and Immunity, St George's, University of London, London, UK.
authors.forename: Wishwanath R A
authors.initials: WR
authors.lastname: Patkee
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Georgina
authors.initials: G
authors.lastname: Carr
authors.affiliation: Institute for Infection and Immunity, St George's, University of London, London, UK.
authors.forename: Emma H
authors.initials: EH
authors.lastname: Baker
authors.affiliation: Institute for Infection and Immunity, St George's, University of London, London, UK.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Baines
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: James P
authors.initials: JP
authors.lastname: Garnett
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D062445:Claudin-1 / Q000235:genetics / Q000378:metabolism; D018920:Coculture Techniques; D017097:Electric Impedance; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000037:antagonists & inhibitors* / Q000633:toxicity; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D062793:Occludin / Q000235:genetics / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000502:physiology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology; D019108:Tight Junctions / Q000187:drug effects* / Q000378:metabolism
chemical_list: C568108:CLDN1 protein, human; D062445:Claudin-1; D007004:Hypoglycemic Agents; C568985:OCLN protein, human; D062793:Occludin; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D008687:Metformin; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D005947:Glucose
keywords: AMPK; P. aeruginosa; airway epithelium; claudin-1; diabetes; glucose; metformin; occludin; respiratory infection; tight junctions
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