The Microbial Bile Acid Metabolite 3-Oxo-LCA Inhibits Colorectal Cancer Progression

Abstract Bile acids (BA) not only influence the gut microbiome composition but are also metabolized by gut bacteria to form various microbial BAs. Among these, 3-oxo-lithocholic acid (3-oxo-LCA) and isoallo-LCA have been reported to modulate host immunity, suppress intestinal pathogens, and provide antiaging benefits, suggesting that they could also affect intestinal epithelial cells and colorectal cancer progression. To investigate the impact of 3-oxo-LCA on intestinal tumorigenesis, we evaluated its activity in vitro on mouse and human colorectal cancer cell lines, as well as primary mouse intestinal organoids and patient-derived colorectal cancer organoids, and in vivo using a genetically engineered mouse model, cell line–derived syngeneic and xenograft tumors, and patient-derived xenografts. 3-Oxo-LCA functioned as a potent FXR agonist that restored FXR signaling both in vitro and in vivo. Activation of FXR signaling reduced the growth of colorectal cancer cell lines and suppressed the proliferation of intestinal stem cells in both mouse organoids and patient-derived colorectal cancer organoids. In the APCMin/+ genetically engineered mouse model, 3-oxo-LCA reduced BA levels, enhanced gut barrier function, decreased tumor burden, and suppressed tumor initiation. Furthermore, 3-oxo-LCA significantly inhibited tumor progression in syngeneic and xenograft mouse models and promoted apoptosis within the tumors. Together, these results underscore the function of 3-oxo-LCA as an FXR agonist with the ability to inhibit colorectal cancer tumorigenesis and progression by modulating epithelial cell growth and death. Significance: The microbial bile acid 3-oxo-LCA activates FXR signaling in intestinal epithelial cells that inhibits cancer stem cell proliferation and induces apoptosis, highlighting the potential of 3-oxo-LCA for treating intestinal tumorigenesis.