Intestinal stem cell dynamics: Nutritional, pharmacological, and epigenetic influences on colorectal cancer development

Williams, Non 2025. Intestinal stem cell dynamics: Nutritional, pharmacological, and epigenetic influences on colorectal cancer development. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Environmental and lifestyle factors strongly influence intestinal homeostasis and colorectal cancer (CRC) risk. In the UK, over half of CRC cases are considered preventable through healthy lifestyle choices, including diet, physical activity, and avoidance of smoking and excessive alcohol. With anti-obesity medications becoming increasingly accessible, it is critical to understand their broader effects on intestinal plasticity and cancer susceptibility. This thesis investigates how diet, pharmacological agents, and epigenetic regulators modulate intestinal stem cell (ISC) behaviour, cancer stem cell (CSC) dynamics, and early CRC development. We show that short-term high-fat diet (HFD) exposure increased ISC stemness, highlighting the rapid adaptability of the intestinal epithelium. Exercise reversed these effects, whereas the anti-obesity peptide LiPR failed to counteract HFD-induced changes. LiPR unexpectedly increased ISC stemness in non-obese, control-diet fed mice, highlighting that anti-obesity compounds can markedly affect intestinal homeostasis, with potential implications for tumorigenesis. Organoid studies revealed direct epithelial targeting, mostly likely due to GPR10 receptor presence in intestinal crypts. The epigenetic regulator MBD2 was identified as a key driver of CSC maintenance. MBD2 knockdown in human CRC cell lines reduced clonogenicity and expression of CSC markers including ALDH1, BCL9, and CD133. ChIP-sequencing revealed repression of differentiation-promoting genes, particularly HOX family members, supporting its role in sustaining CSC phenotypes and supporting its potential as a therapeutic target. Patient-derived organoids from polyp tissue demonstrated inter- and intra-patient heterogeneity in gene expression and MBD2 isoform usage, emphasizing the complexity of early CRC development and the need for personalized prevention strategies. Together, these findings demonstrate that lifestyle interventions and pharmacological agents can profoundly influence ISC dynamics, while MBD2 represents a promising target for CRC prevention and therapy. This work provides mechanistic insight into how environmental and epigenetic factors shape CRC risk and progression, supporting strategies for precision prevention and clinical intervention.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	6 February 2026
Last Modified:	06 Feb 2026 13:43
URI:	https://orca.cardiff.ac.uk/id/eprint/184481

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