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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE294276 | GEO | 2025/08/14

REPOSITORIES: GEO

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Project description:Mouse models of intestinal crypt cell differentiation and tumorigenesis have been used to characterize the molecular mechanisms underlying both processes. DNA methylation is a key epigenetic mark and plays an important role in cell identity and differentiation programs and cancer. To get insights into the dynamics of cell differentiation and malignant transformation we have compared the DNA methylation profiles along the mouse small intestine crypt and early stages of carcinogenesis. Genome-scale analysis of DNA methylation together with microarray gene expression have been applied to compare intestinal crypt stem cells (EphB2positive), differentiated cells (EphB2negative), ApcMin/+ adenomas and the corresponding non-tumor adjacent tissue, together with small and large intestine samples and the colon cancer cell line CT26. Compared with late stages, small intestine crypt differentiation and early stages of carcinogenesis display few and relatively small changes in DNA methylation. Hypermethylated loci are largely shared by the two processes and affect the proximities of promoter and enhancer regions, with enrichment in genes regulated by PRC2 and associated with the intestinal stem cell signature. The hypermethylation is progressive, with minute levels in differentiated cells, as compared with intestinal stem cells, and reaching full methylation in advanced stages. Hypomethylation shows different signatures in differentiation and cancer and is already present in the non-tumor tissue adjacent to the adenomas in ApcMin/+mice, but at lower levels than advanced cancers. Taking into account the parallelisms between human and mouse intestinal carcinogenesis, this study provides a reference framework to interpret the alterations found in human cancer. We have analyzed ApcMin/+ adenomas and the corresponding non-tumor adjacent tissue, together with small and large intestine samples and the colon cancer cell line CT26. Samples were in triplicates, except for tissue adjacent to adenoma (in duplicates).

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

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