Title:

An investigation into the effect of artificial sweeteners on Pseudomonas aeruginosa on the lung epithelium

Summary:

In recent years, artificial sweeteners have become increasingly popular as a non-caloric additive to sweeten foods and drinks.  We have previously shown that artificial sweeteners cause intestinal barrier disruption and leak, associated with sepsis (1). Other studies have demonstrated increased glucose tolerance following exposure to artificial sweeteners which is strongly linked to the onset and worsening of diabetes (2-5). Furthermore, recent research in our lab demonstrated a negative impact of artificial sweeteners commonly found in the diet on two laboratory strains of gut bacteria (6).

Pseudomonas aeruginosa has been identified as one of the top global priority bacteria with urgent need for novel therapeutic intervention (7,8).  This is largely because P. aeruginosa infections are becoming harder to treat due to their natural resistance to many antibiotics and the increasing prevalence of multi-drug resistant strains worldwide.  We have previously demonstrated that P. aeruginosa infection causes acute respiratory distress syndrome with inflammation of the pulmonary epithelium and significant edema formation (9, 10). Given the role of this bacteria in lung injury, and our previous studies with gut bacteria we hypothesise that exposure of P. aeruginosa to artificial sweeteners will significantly increase the pathogenic capacity of the bacteria.

Studies will be split into two aims:

Aim 1: identify the effect of artificial sweeteners on P. aeruginosa growth and ability to form a biofilm;

Aim 2: assess the impact of sweeteners on the ability of P. aeruginosa to invade human lung epithelial cells.

Required knowledge:

• Experience in microbiological techniques such as bacterial culture, media preparation and biofilm assays would be advantageous as would knowledge and experience of mammalian cell culture. 

Supervisors:

Day-to-day supervisor: Caray A Walker (caray.walker@aru.ac.uk) Anglia Ruskin University, School of Life Sciences.

Co-supervisor: Havovi Chichger (havovi.chichger@aru.ac.uk) Anglia Ruskin University, School of Life Sciences.

Co-supervisor: Martin Welch (mw240@cam.ac.uk) University of Cambridge, Department of Biochemistry.

References:

(1)        Shil A, Olusanya O, Ghufoor Z, Forson B, Marks J, Chichger H. Artificial Sweeteners Disrupt Tight Junctions and Barrier Function in the Intestinal Epithelium through Activation of the Sweet Taste Receptor, T1R3. Nutrients. 2020 Jun 22;12(6):1862. doi: 10.3390/nu12061862. PMID: 32580504; PMCID: PMC7353258.

(2)        Suez J, Korem T, Zeevi D, Zilberman-Schapira G, Thaiss CA, Maza O, Israeli D, Zmora N, Gilad S, Weinberger A, Kuperman Y, Harmelin A, Kolodkin-Gal I, Shapiro H, Halpern Z, Segal E, Elinav E. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature. 2014 Oct 9;514(7521):181-6. doi: 10.1038/nature13793. Epub 2014 Sep 17. PMID: 25231862.

 (3)       Suez J, Korem T, Zilberman-Schapira G, Segal E, Elinav E. Non-caloric artificial sweeteners and the microbiome: findings and challenges. Gut Microbes. 2015;6(2):149-55. doi: 10.1080/19490976.2015.1017700. Epub 2015 Apr 1. PMID: 25831243; PMCID: PMC4615743.

 (4)       Frankenfeld CL, Sikaroodi M, Lamb E, Shoemaker S, Gillevet PM. High-intensity sweetener consumption and gut microbiome content and predicted gene function in a cross-sectional study of adults in the United States. Ann Epidemiol. 2015 Oct;25(10):736-42.e4. doi: 10.1016/j.annepidem.2015.06.083. Epub 2015 Jul 17. PMID: 26272781.

 (5)       Bian X, Chi L, Gao B, Tu P, Ru H, Lu K. Gut Microbiome Response to Sucralose and Its Potential Role in Inducing Liver Inflammation in Mice. Front Physiol. 2017 Jul 24;8:487. doi: 10.3389/fphys.2017.00487. PMID: 28790923; PMCID: PMC5522834.

 (6)       Shil A, Chichger H. Artificial Sweeteners Negatively Regulate Pathogenic Characteristics of Two Model Gut Bacteria, E. coli and E. faecalis. Int J Mol Sci. 2021 May 15;22(10):5228. doi: 10.3390/ijms22105228. PMID: 34063332; PMCID: PMC8156656.

 (7)       US CDC 2019; Antimicrobial Resistance Collaborators 2022, Lancet.

 (8)       WHO,www.who.int/medicines/publications/WHO-PPL-Short_Summary_25Feb-ET_NM_WHO..., Date: 2017

 (9)       Chichger H, Braza J, Duong H, Harrington EO. SH2 domain-containing protein tyrosine phosphatase 2 and focal adhesion kinase protein interactions regulate pulmonary endothelium barrier function. Am J Respir Cell Mol Biol. 2015 Jun;52(6):695-707. doi: 10.1165/rcmb.2013-0489OC. PMID: 25317600; PMCID: PMC4491126.

 (10)     Chichger H, Braza J, Duong H, Boni G, Harrington EO. Select Rab GTPases Regulate the Pulmonary Endothelium via Endosomal Trafficking of Vascular Endothelial-Cadherin. Am J Respir Cell Mol Biol. 2016 Jun;54(6):769-81. doi: 10.1165/rcmb.2015-0286OC. PMID: 26551054; PMCID: PMC4942219.