Microbial Bile acid metabolite, 3-oxo-LCA, prohibits colorectal cancer progression

Objective: Bile acids (BAs) not only influence gut microbiome composition but are also metabolized by gut bacteria to form various microbial BAs. Among these, 3-oxo-lithocholic acid (-oxo-LCA) and isoalloLCA have been reported to modulate host immunity, suppress intestinal pathogens, and provide anti-aging benefits. However, their specific effects on intestinal epithelial cells (IECs) and their role in colorectal cancer (CRC) progression remain unclear. Design: To investigate the impact of 3-oxo-LCA on intestinal tumorigenesis, we examined its effects on the growth of mouse and human CRC cell lines (CT26, MC38, HCT116), as well as on primary mouse intestinal organoids and patient-derived CRC organoids (PDCOs). Additionally, we evaluated its role in vivo using APCMin/+ mice and multiple CRC models, including syngeneic CT26 and MC38 models, as well as HCT116 and PDX-derived xenografts in NSG (immunodeficient) mice. Results: Our findings show that 3-oxo-LCA is a potent FXR agonist that restores FXR signaling both in vitro and in vivo. This results in reduced growth of CRC cell lines and suppression of intestinal stem cell (ISC)’s proliferation in both mouse organoids and PDCOs. In APCMin/+ mice, 3-oxo-LCA reduced BA levels, enhanced gut barrier function, decreased tumor burden, and blocked tumor initiation. Furthermore, it significantly inhibited tumor progression in syngeneic and xenograft mouse models and promoted apoptosis within the tumors, enhancing cancer cell death. Conclusion: These results underscore the therapeutic potential of 3-oxo-LCA as a novel FXR agonist for CRC treatment, with its ability to inhibit tumorigenesis and progression by modulating epithelial cell proliferation and inducing apoptosis.