Molecular and Microenvironmental Drivers of Gastrointestinal Diseases
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2024-12-09
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Abstract
The gastrointestinal tract consists of interconnected organs responsible for digestion and nutrient absorption, with the small intestine and colon being the largest components of this system. Although these organs share many similarities, their specialized functions in maintaining homeostasis contribute to varying disease susceptibilities. This dissertation examines the molecular and microenvironmental factors, such as upregulated genes, emergent cell types, and microbial influences, in the pathogenesis of colorectal cancer and Crohn’s disease.
In colorectal cancer, the tumor microenvironment, composed primarily of epithelial, immune, and mesenchymal cells, plays a crucial role in disease progression. This work investigated the role of cancer-associated fibroblasts in colorectal tumorigenesis. Through single-cell RNA-sequencing and multiplex immunofluorescence imaging, we characterized cancer-associated fibroblast subpopulations across two mouse models. In advanced lesions, cancer-associated fibroblasts exhibited pro-inflammatory gene expression and were spatially associated with tumor cells. Computational analysis of ligand-receptor interactions revealed significant communication between cancer-associated fibroblasts and tumor cells, suggesting cancer-associated fibroblasts are key drivers of tumor progression.
This dissertation also explores how regionalization of the gut influences susceptibility to chronic intestinal inflammation, such as Crohn’s disease. Although the gastrointestinal tract varies in structure and function across regions, the factors driving inflammation in specific areas remain unclear. Using a TNF-overexpressing Crohn's disease mouse model (TnfΔARE/+), we investigated the role of genetic and environmental factors in region-specific disease, focusing on the terminal ileum and ascending colon, the two most affected regions in human Crohn’s disease. We identified Chlamydia muridarum as necessary and sufficient for disease manifestation in the ascending colon, with inflammation driven by goblet cell expression of indoleamine 2,3-dioxygenase (IDO1) in genetically susceptible hosts. Finally, we investigated the role of Paneth cells in terminal ileal inflammation. While Paneth cells upregulate IDO1 in the inflamed ileum, three independent ablation models demonstrate that Paneth cells are dispensable for the development of ileal inflammation in the TnfΔARE/+ model.
Overall, these findings provide new insights into the molecular and environmental factors driving colorectal cancer and Crohn’s disease, highlighting the roles of cancer-associated fibroblasts, microbes, upregulation of IDO1, and regional gut differences in disease susceptibility and progression.
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inflammation, cancer, gastrointestinal, Crohn's disease, pathobiont, Chlamydia, microbiome, epithelial cells