Primary supervisor - Dr Stephanie Schüller
Colorectal cancer (CRC) is the third most common and second most fatal cancer globally. Most cases of CRC are not hereditary but influenced by lifestyle factors and changes in the gut microbiome. Importantly, 5-10% of CRCs have been linked to E. coli strains producing the metabolite colibactin which causes DNA damage and mutagenesis in colonic epithelial cells. Interestingly, recent work has shown that colibactin expression is highest under microaerobic conditions similar to those in the colon. Furthermore, inflammation and mucus depletion promote colibactin production and carcinogenesis indicating a role of the gut environment in regulation of colibactin expression. In addition to colonic oncogenesis, colibactin also kills certain gut bacteria suggesting an evolutionary role in interbacterial competition. Given the impact of colibactin and the microbiome in CRC development, it is crucial to understand how colibactin production is regulated in the human gut and how it affects the gut microbiome.
In this PhD project funded by Big C cancer charity, we will use a physiologically relevant microaerobic, mucus-producing human colonic cell and organoid model which allows co-culture with oxygen-sensitive gut bacteria to investigate 1) the influence of chemical cues and commensal bacteria on colibactin expression, 2) the interaction of genotoxic E. coli with the colonic epithelium, and 3) the impact of genotoxic E. coli on the gut microbiome.
Taken together, insights gained from this work will inform the development of therapies targeted at E. coli-associated CRC through colibactin inhibition and the identification of bacterial biomarkers for high-risk populations.
This project will be suited for a motivated student with a background in microbiology & cell biology and relevant research experience. You will join an interdisciplinary and supportive research environment at the UEA Medical School and closely collaborate with the teams of Prof Nathalie Juge (Quadram Institute) and Prof Jean-Philippe Nougayrède (University of Toulouse). Expert training in bacterial, intestinal cell and organoid culture, evaluation of epithelial function, molecular biology, microbiome analysis and bioimaging will be provided.
Entry requirements
The standard minimum entry requirement is 2:1 in Biological Sciences.
References
i) Nougayrède JP, Homburg S, Taieb F, Boury M, Brzuszkiewicz E, Gottschalk G, et al. (2006) Escherichia coli induces DNA double-strand breaks in eukaryotic cells. Science313(5788):848-51.
ii) McGrath CJ, Laveckis E, Bell A, Crost E, Juge N & Schüller S. (2022) Development of a novel human intestinal model to elucidate the effect of anaerobic commensals on Escherichia coli infection. Dis Model Mech. 15(4):dmm049365.
iii) Bossuet N, Guyonnet C, Chagneau CV, Tang-Fichaux M, Penary M, Loubet D, Branchu P, Oswald E & Nougayrede JP (2023) Oxygen concentration modulates colibactin production. Gut microbes. 2023;15(1):2222437.
iv) Sato T et al. (2011) Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium. Gastroenterology 141(5):1762-72.
v) Krsek D, Yara DA, Hrbáčková H, Daniel O, Mančíková A, Schüller S* & Bielaszewska M*. (2023) Translocation of outer membrane vesicles from enterohemorrhagic Escherichia coli O157 across the intestinal epithelial barrier. Front Microbiol. 14:1198945.
Additional Funding Information
This is a fully funded studentship which covers tuition fees at Home fee rate and provides an annual stipend of £19,162 and £1,000 per annum to support research training.