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

Nov 12, 2024Proceedings of the National Academy of Sciences of the United States of America

Opposite roles of two gut bacteria–changed bile acids in intestinal tumor growth

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Abstract

High-fat diet treatment in mice elevated levels of 7-oxo-deoxycholic acid (7-oxo-DCA) and isoDCA, with 7-oxo-DCA promoting cancer cell growth and isoDCA suppressing it.

7-oxo-DCA levels increase while isoDCA levels decrease during intestinal tumorigenesis in mice.
7-oxo-DCA promotes the proliferation of , whereas isoDCA inhibits it.
Mice given 7-oxo-DCA showed heightened gut permeability and increased tumor burden compared to those treated with isoDCA.
IsoDCA was found to protect the gut barrier and reduce tumor loads.
7-oxo-DCA acts as a natural antagonist of (FXR), downregulating its signaling, while isoDCA serves as a potent FXR agonist, upregulating its signaling.
Both bile acids alter the bile acid pool and shift the gut microbiome composition.

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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 in organoids derived from WT andmice, as well as in patient-derived colon cancer organoids. Themice 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 (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. APC Min/+ APC Min/+

Key numbers

13.795 μM

IC50 of 7-oxo-DCA

Half-maximal inhibitory concentration for 7-oxo-DCA in activating signaling.

4.384 μM

EC50 of isoDCA

Half-maximal effective concentration for isoDCA in activating signaling.

notable increase

Increased tumor numbers

7-oxo-DCA administration led to a significant rise in tumor numbers in treated mice.

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

Abstract

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