Title Page
Abstract
Contents
Introduction 9
1. Intestinal stem cells and cancer stem cells 9
2. Intestinal stem cell niche 10
3. Intestinal mesenchymal stromal cells 11
4. Wnt signaling pathway 12
5. HFD and intestinal stem cells 13
6. Diet and gut microbiota 15
7. Bile acid metabolism 17
8. The rationale of my study 18
Materials and Methods 19
Results 30
HFD leads to pathological conditions in colon. 30
HFD amplifies CD44 expression and Wnt signaling in colonic crypts 34
HFD stimulates Wnt2b production and cancer-associated properties in colonic MSCs 40
HFD-derived MSCs induces CSCs characteristics in colon organoids 45
Metabolites from altered gut microbiota by HFD caused hyper Wnt2b secretion from MSCs 49
Increased FFA by HFD does not affect the secretion of Wnt2b from MSCs 53
HFD-derived gut microbiota increased the BA metabolites 57
BAs-FXR axis stimulates Wnt2b production in colonic MSCs 60
Discussion 64
Conclusion 68
Reference 69
국문 요약 77
Figure 1. Intestinal stem cell niche in the colon. 10
Figure 2. Intestinal tumorigenesis increased by HFD. 14
Figure 3. The role of dietary factors and gut microbiota in intestinal homeostasis. 16
Figure 4. Classic bile acid metabolism. 18
Figure 5. Dietary composition and alteration of body weight. 31
Figure 6. HFD resulted in pathological conditions in the colon. 32
Figure 7. Increased incidence rate of colorectal cancer in HFD-fed mice. 33
Figure 8. HFD stimulated proliferation of crypt cells. 35
Figure 9. HFD induced abnormal stemness and CSC. 37
Figure 10. The expression level of various ISC niche signal-related genes. 38
Figure 11. HFD amplified Wnt/β-catenin signaling in colonic crypts. 39
Figure 12. HFD promoted the Wnt2b production in colonic MSCs. 41
Figure 13. The expansion of sub-epithelial MSCs in colon of HFD-fed mice. 42
Figure 14. HFD-derived colonic MSCs have the CAF-like properties. 43
Figure 15. HFD enhanced glycolytic activity in colonic MSCs. 44
Figure 16. HFD-derived colonic MSCs stimulate proliferation and CSCs-related gene expression in colon organoids. 47
Figure 17. Effects of Wnt antagonists in the organogenesis by MSCs. 48
Figure 18. Regulation of Wnt2b by cecal microbial products. 50
Figure 19. HFD led to a change in gut microbiota composition and community. 52
Figure 20. The analysis of short-chain fatty acid. 54
Figure 21. The increased FFA level in CMP of mice fed HFD. 55
Figure 22. FFA did not promote Wnt2b production from colonic MSCs. 56
Figure 23. Expansion of bacteria with BSH activity induced by HFD. 58
Figure 24. HFD alters the composition of BAs through gut microbiota. 59
Figure 25. Activated FXR signal pathway in HFD-fed mice. 61
Figure 26. BAs regulate Wnt2b production in colonic MSCs via FXR. 63