The link between these bile acids and colon cancer risk was recently uncovered as University of Wisconsin-Madison scientists sought to better understand the relationship between gut microbes and our bodies.

In many ways, that relationship revolves around a specific protein called the farnesoid X receptor, or FXR, which helps maintain a healthy gut through its intimate relationship with bile acids. FXR controls the production of bile acids in the liver, but it also responds in different ways to the presence of various bile acids that microbes have modified.

“Some microbial bile acids support FXR’s function, while others antagonize it,” says Ting Fu, an assistant professor in the UW-Madison School of Pharmacy. Fu and her colleagues previously identified the protein as a promising drug target for treating inflammatory bowel disease and colitis, a debilitating gastrointestinal condition that raises the risk for colon cancer.

Now, a team led by Fu, pharmacy professor Jiaoyang Jiang and Dustin Deming, an associate professor in the UW School of Medicine and Public Health, have identified two microbial bile acids that have opposing effects on FXR during the development of tumors in the intestines, with one supporting its function and the other inhibiting it.

Importantly, the bile acids’ influence on FXR translates to their effect on the growth of tumors, but with a twist. The bile acid that supports the protein’s function slows the growth of cancer, while the bile acid that inhibits FXR acts as fuel for the tumors.

These results were consistent across mouse models of colon cancer the researchers studied, along with organoids — lab-grown miniature organs — derived from human colon cancer patients.

This is the first time these specific microbial bile acids have been linked to either the development or protection against colorectal cancer. The team’s findings recently appeared in the journal of the Proceedings of the National Academy of Sciences. The results now provide a roadmap for investigating potential new cancer detection methods and novel treatments.

“Understanding these complex mechanisms is a significant step toward improving early detection and developing targeted therapies for colorectal cancer,” says Xingchen Dong, a postdoctoral researcher in the UW pharmacy school and lead author of the paper. “This study not only deepens our comprehension of the intricate relationship between gut microbiota and cancer, but also opens new avenues for medical advancements that could potentially benefit millions worldwide.”

Fu says the bile acids’ opposing roles in the development of intestinal tumors underscores how deeply complex the community of microbes within our guts is.

“I think it’s fascinating that microbes can modify bile acids in this way and have such a big impact on our body,” she said. “We have more microbes in our body than our own cells, so when something happens to their environment, like the growth of a tumor, some good ones try to help us correct it. But that totally depends on what they need, nutrition-wise.”

This research funded by University of Wisconsin-Madison startup grants (AAI3795, AAI3894), UWCCC startup support (AAI5122), UW fall competition support from Wisconsin Alumni Research Foundation (AAL8735), Badger Challenge award (AAM7958), PhRMA foundation Faculty Starter Grant (2024-FSGDS-1161699), American Cancer Society Coaches vs. Cancer Bo Ryan-Jay Holliday Families Fund Research Scholar Grant (RSG-23-1150338-01), Margaret Q. Landenberger Research Foundation (AAM7699), and NIH 1R37CA288447-01.