This PhD thesis Frank Sun explores cellular heterogeneity and therapeutic responses in inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC), two chronic, immune-mediated diseases. Using advanced single-cell RNA sequencing and metagenomic techniques, the research provides insights into the complex pathophysiology of these diseases.
The first part focuses on the disease mechanisms of IBD and PSC. It identifies distinct stromal cell subpopulations in inflammatory and fibrostenotic CD, elucidates the unique cellular features of PSC-associated IBD, investigates epithelial LND cells characterized by high expression of LND, LCN2, NOS2, and DUOX2 across CD, ulcerative colitis (UC), and PSC-associated IBD, and explores cholangiocyte subsets in early PSC. These findings enhance the understanding of inflammation, epithelial cell contributions, and fibrosis, revealing potential therapeutic targets.
The second part examines therapeutic responses in IBD. It characterizes cellular signatures associated to responses to vedolizumab in ulcerative colitis at baseline and investigates the role of microbial acetyltransferase gene families in the gut microbiota, which have been associated with 5-aminosalicylic acid (5-ASA) treatment failure in IBD. However, these associations could not be replicated in an independent Dutch cohort, underscoring the need for further validation in diverse populations.
This thesis advances knowledge of disease mechanisms and therapeutic responses, offering a foundation for developing personalized treatments for IBD and PSC.
