PhD Studentship: Investigating the Role of the Microbiota in Crohn’s Disease by Using Organoid Models (SCHULLERS_U24HRTMED)

Primary supervisor - Dr Stephanie Schüller

Crohn’s Disease (CD) is a chronic inflammatory bowel disorder affecting > 120,000 people in the UK. It is often diagnosed in young adulthood, and symptoms include chronic abdominal pain, diarrhoea, and weight loss. Current therapies are aimed at reducing inflammation but can have severe side effects. There is no cure, and many patients require surgery.
 
The precise causes for CD remain unknown, but research shows that CD patients harbour genetic mutations which reduce bacterial clearance. In addition, they exhibit a lower variety in gut microbiota and leaky intestinal epithelium which promotes inflammation. It is currently unclear if the disturbed microbiota is a cause or consequence of CD due to a lack of biologically relevant experimental systems.

In this PhD project, we will establish a new model to decipher microbiota-epithelium interactions in CD by employing human stem cell-derived intestinal organoids (colonoids) which form epithelia with donor-specific genetic profiles. To support survival of oxygen-sensitive bacteria, we will employ a vertical diffusion chamber (VDC) established in the Schüller lab, which maintains low oxygen levels on one side of the epithelium while providing oxygenation to the other. After adapting and validating the VDC for long-term microbiota-colonoid culture, we will apply the new system to determine the effect of microbiota from CD or healthy donors (HD) on colonoids from CD or HD with respect to microbiota composition, metabolite production, epithelial host response and inflammation. Functional pathways will be followed up by targeted experimentation. Results from this study will inform new therapies targeted at restoring microbiota-epithelium homeostasis in CD and reduce animal use in research.

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 Prof Narbad’s group at the Quadram Institute. Expert training in bacterial and organoid culture, molecular biology and bioimaging will be provided. 

Entry requirements

The standard minimum entry requirement is 2:1 in Biological Sciences.

Mode of study: Full-time 

Start date: February 2025

References

1. Stange EF, Schroeder BO. (2019) Microbiota and mucosal defense in IBD: an update. Expert Rev Gastroenterol Hepatol. 13(10):963-76.
2. 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.
3. 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.
4. Schüller S, Phillips AD. (2010) Microaerobic conditions enhance type III secretion and adherence of enterohaemorrhagic Escherichia coli to polarized human intestinal epithelial cells. Environ Microbiol. (9):2426-35.
5. 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.

Funding Details

Additional Funding Information

This is a fully funded three-year PhD studentship, consisting of Home fees, an annual stipend of £19,180 and £1,000 per annum to support research training. 

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