It is known that gut microbes and their metabolites are closely linked to the development and progression of colorectal cancer and the effectiveness of immunotherapy. Gut microbes can convert primary bile acids from the host into various bile acid metabolites, such as 3-oxolithocholic acid (3-oxo-LCA), through reactions such as dehydrogenation and epimerization.
Previous studies have shown that 3-oxo-LCA can inhibit the differentiation of pro-inflammatory Th17 cells by binding to the retinoic acid-related orphan receptor γt (RORγt), thereby improving intestinal immunity. However, whether 3-oxo-LCA can inhibit the development and progression of colorectal cancer remains unclear. Based on this, Fu Ting's team at the University of Wisconsin recently published an important study, finding that the bile acid metabolite 3-oxo-LCA can indeed inhibit the development and progression of colorectal cancer. The related research was published in Cancer Research.
Specifically, by establishing multiple in vitro colorectal cancer cell lines and organoids, as well as multiple in vivo colorectal cancer mouse models, they discovered that 3-oxo-LCA, as an activator of the bile acid receptor FXR (farnesoid X receptor), can inhibit the Wnt oncogenic pathway by activating FXR signaling. This not only inhibited colorectal cancer cell proliferation in vitro but also improved intestinal barrier function in colorectal cancer-bearing mice, reduced tumor burden, and inhibited tumor progression.
In fact, a wide variety of bile acid metabolites are produced by gut microbes. Previous research teams have found that 7-oxodeoxycholic acid (7-oxo-DCA), as an FXR antagonist, can inhibit the FXR signaling pathway and activate the Wnt pathway, regulating intestinal stem cell proliferation and promoting the development and progression of colorectal cancer.
In this study, researchers sought to investigate whether 3-oxo-LCA, a bile acid metabolite known to have beneficial effects on intestinal immunity, could inhibit abnormal intestinal epithelial cell proliferation and tumor progression by activating the FXR signaling pathway.
First, at the metabolic level, the researchers observed significantly reduced levels of 3-oxo-LCA in the feces of patients with inflammatory bowel disease and colorectal adenomas. Subsequently, using luciferase reporter gene assays, the researchers demonstrated that 3-oxo-LCA selectively activated the FXR signaling pathway, and its ability to activate FXR was stronger than that of chenodeoxycholic acid (CDCA), a natural FXR agonist.
Further, they investigated the effects of 3-oxo-LCA on intestinal stem cell proliferation and the development and progression of colorectal cancer. The researchers generated multiple in vitro colorectal cancer cell lines and intestinal organoids, as well as multiple in vivo colorectal cancer mouse models.
The results showed that 3-oxo-LCA significantly inhibited tumor cell proliferation and induced apoptosis in multiple human (HCT116) and mouse (CT26, MC38) colorectal cancer cell lines. Furthermore, wound healing experiments demonstrated that 3-oxo-LCA significantly inhibited tumor cell migration and invasion. Gene expression analysis further confirmed that 3-oxo-LCA effectively activated FXR and inhibited the Wnt signaling pathway. These results were observed in both primary mouse intestinal organoid models and patient-derived colorectal cancer organoid models.
Figure 1. 3-oxo-LCA inhibits tumor progression in HCT116-xenograft NSG mice. (Sun F, et al., 2025)
Similarly, in a genetically engineered colorectal cancer mouse model (APCMin/+), syngeneic and xenograft mouse models derived from colorectal cancer cell lines, and a patient-derived colorectal cancer xenograft mouse model, the researchers found that 3-oxo-LCA not only enhanced intestinal barrier function but also reduced tumor burden and inhibited colorectal cancer progression. Finally, using RNA sequencing of HCT116 xenografts, the researchers further confirmed at the genetic level that 3-oxo-LCA can activate FXR target genes (such as SHP), inhibit Wnt signaling and cell cycle-related genes (such as LRP5, DVL2/3, and CSNK1E), and upregulate genes involved in the apoptosis pathway (such as CASP3, BAK1, and BAX), thereby regulating the growth and apoptosis of intestinal stem cells and ultimately inhibiting the occurrence and progression of colorectal cancer.
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In summary, this study demonstrates for the first time that 3-oxo-LCA, a bile acid metabolite converted by gut microbes, can act as a potent FXR agonist, inhibiting the occurrence and progression of colorectal cancer by activating the FXR signaling pathway. This result also provides a theoretical basis for the future development of precise colorectal cancer prevention and treatment approaches based on the bile acid signaling pathway.
Reference
Sun F, et al. The Microbial Bile Acid Metabolite 3-oxo-LCA Inhibits Colorectal Cancer Progression. Cancer Research, 2025.