A High-Fat Diet Activates the BAs-FXR Axis and Triggers Cancer-Associated Fibroblast Properties in the ColonSummary

• Published in: Cellular and molecular gastroenterology and hepatology Vol. 13; no. 4; pp. 1141 - 1159
• Main Authors: Tae-Young Kim, Seungil Kim, Yeji Kim, Yong-Soo Lee, Sohyeon Lee, Su-Hyun Lee, Mi-Na Kweon
• Format: Journal Article
• Language: English
• Published: Elsevier 01.01.2022
• Subjects: Cancer Stem Cells; Gut Microbiome; Mesenchymal Stromal Cells; Wnt2b
• ISSN: 2352-345X; 2352-345X

Background & Aims: Dietary signals are known to modulate stemness and tumorigenicity of intestinal progenitors; however, the impact of a high-fat diet (HFD) on the intestinal stem cell (ISC) niche and its association with colorectal cancer remains unclear. Thus, we aimed to investigate how a HFD affects the ISC niche and its regulatory factors. Methods: Mice were fed a purified diet (PD) or HFD for 2 months. The expression levels of ISC-related markers, ISC-supportive signals, and Wnt2b were assessed with real-time quantitative polymerase chain reaction, in situ hybridization, and immunofluorescence staining. RNA sequencing and metabolic function were analyzed in mesenchymal stromal cells (MSCs) from PD- and HFD-fed mice. Fecal microbiota were analyzed by 16s rRNA sequencing. Bile salt hydrolase activity and bile acid (BA) levels were measured. Results: We 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 PD. Within the ISC niche, MSCs were expanded and secreted predominant levels of Wnt2b in the colon of HFD-fed mice. Of note, increased energy metabolism and cancer-associated fibroblast (CAF)-like properties were found in the colonic MSCs of HFD-fed mice. Moreover, colonic MSCs from HFD-fed mice promoted the growth of tumorigenic properties and accelerated the expression of cancer stem cell (CSC)-related markers in colon organoids. In particular, production of primary and secondary BAs was increased through the expansion of bile salt hydrolase-encoding bacteria in HFD-fed mice. Most importantly, BAs-FXR interaction stimulated Wnt2b production in colonic CAF-like MSCs. Conclusions: HFD-induced colonic CAF-like MSCs play an indispensable role in balancing the properties of CSCs through activation of the BAs-FXR axis.