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

Abstract Bile acids (BAs) 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 anti-aging benefits, suggesting that they could also affect intestinal epithelial cells and colorectal cancer (CRC) progression. To investigate the impact of 3-oxo-LCA on intestinal tumorigenesis, we evaluated its activity in vitro on mouse and human CRC cell lines, as well as primary mouse intestinal organoids and patient-derived CRC organoids (PDCOs), and in vivo using a genetically engineered mouse model (GEMM), 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 CRC cell lines and suppressed the proliferation of intestinal stem cells in both mouse organoids and PDCOs. In the APCMin/+ GEMM, 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 CRC tumorigenesis and progression by modulating epithelial cell growth and death.