고지방식이에 의한 대장 섬유아세포 조절 기전 연구

Abstract

Dietary factors are known to modulate stemness and tumorigenicity of intestinal progenitors. Previous studies demonstrated that high-fat diet (HFD) enhanced numbers of intestinal stem cells (ISCs) and further promoted primary and metastatic colorectal cancer. However, little is known how HFD affects ISC niche which might be involved in initiation of colorectal cancer. Additionally, it is known that HFD can cause dysbiosis in the gut microbiota, resulting in a reduction of diversity and an imbalance in the composition of the gut microbiota. Recent studies have indicated that alterations in gut microbiota induced by HFD can have an impact on intestinal tumorigenesis, but the mechanism underlying the relationship between gut microbiota and colorectal cancer remains unclear. Therefore, understanding the relationship between HFD, ISC niche, and gut microbiota may provide clues for the development of HFD-induced colorectal cancer. In this study, I found that expression of CD44 and Wnt signal-related genes was higher in the colonic crypts of HFD-fed mice than in those fed a purified diet. Within the ISC niche, mesenchymal stromal cells (MSCs) were expanded and secreted predominant levels of Wnt2b in the colon of HFD-fed mice. Of note, increased energy metabolism and cancer-associated fibroblasts (CAFs)-like properties were found in the colonic MSCs of HFD-fed mice. Moreover, colonic MSC from HFD-fed mice promoted the growth of tumorigenic properties and accelerated the expression of cancer stem cells (CSCs)-related markers in colon organoids. In particular, production of deconjugated and secondary bile acids (BAs) was increased through the expansion of bile salt hydrolase-encoding bacteria in HFD-fed mice. Most importantly, BAs-farnesoid X receptor (FXR) interaction stimulated Wnt2b production in colonic CAF-like MSCs. These findings suggest that gut microbiota-mediated BAs-FXR signaling could be a contributing risk factor for HFD-induced colorectal cancer. Keywords: HFD; CSCs; MSCs, gut microbiota, BAs, FXR