The dichotomous roles of microbial-modified bile acids 7-oxo-DCA and isoDCA in intestinal tumorigenesis.

Abstract

The gut microbiota has a significant impact on the development and function of intestinal epithelial cells (IECs) by modifying bile acid (BA) metabolites. Recently, specific gut microbiome-derived BAs, such as 7-oxo-deoxycholic acid (7-oxo-DCA) and isodeoxycholic acid (isoDCA), have been identified to be shifted inversely in colitis and hepatic liver diseases. Although the responsible gut microbes have been identified, metabolites' effects on IECs remain largely unclear. We found that although high-fat diet treatment in mice elevated both 7-oxo-DCA and isoDCA levels, during intestinal tumorigenesis, 7-oxo-DCA levels rise while isoDCA levels decrease. Interestingly, 7-oxo-DCA promotes cancer cell growth, while isoDCA suppresses it. Moreover, 7-oxo-DCA promotes whereas isoDCA inhibits the proliferation of intestinal stem cells in organoids derived from WT and <i>APC^Min/+</i> mice, as well as in patient-derived colon cancer organoids. The <i>APC^Min/+</i> mice administered with 7-oxo-DCA heightened gut permeability and increased tumor burden, whereas isoDCA protected gut barrier and reduced tumor loads. Both BAs reshape the BA pool and shifted gut microbiome. Mechanistically, we identified 7-oxo-DCA as a natural antagonist of Farnesoid X Receptor (FXR) to downregulate FXR signaling, as opposed to isoDCA, which is a potent FXR agonist to upregulate FXR signaling. In conclusion, we unveiled the opposing roles of 7-oxo-DCA and isoDCA to promote or inhibit intestinal tumorigenesis, respectively. Manipulating the BA-FXR axis during tumor initiation and progression holds great promise for developing innovative diagnostic and therapeutic approaches for the treatment of colorectal cancer.