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Metformin prevents the effects of Pseudomonas aeruginosa on airway epithelial tight junctions and restricts hyperglycaemia-induced bacterial growth

Lookup NU author(s): Dr Georgina Carr, Dr James Garnett

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.


Publication metadata

Author(s): Patkee WRA, Carr G, Baker EH, Baines DL, Garnett JP

Publication type: Article

Publication status: Published

Journal: Journal of Cellular and Molecular Medicine

Year: 2016

Volume: 20

Issue: 4

Pages: 758-764

Print publication date: 01/04/2016

Online publication date: 02/02/2016

Acceptance date: 07/12/2015

ISSN (print): 1582-1838

ISSN (electronic): 1582-4934

Publisher: Wiley-Blackwell

URL: http://dx.doi.org/10.1111/jcmm.12784

DOI: 10.1111/jcmm.12784


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