Gut bacteria turn bile acids into allies against cancer

Bacteria naturally present in the human intestine, known as the gut microbiota, can transform cholesterol-derived bile acids into powerful metabolites that strengthen anti-cancer immunity by blocking androgen signaling, according to a preclinical study led by Weill Cornell Medicine investigators. The study was published on April 15 in Cell.

"I was very surprised by our findings. As far as I know, no one has previously discovered molecules like these bile acids that can interact with the androgen receptor in this way," said co-senior author Dr. Chun-Jun Guo, an associate professor of immunology in medicine in the Division of Gastroenterology and Hepatology and a scientist at the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine. Dr. Wen-Bing Jin, formerly a postdoctoral associate, and Dr. Leyi Xiao, a current postdoctoral associate in Dr. Guo's lab, are the co-first authors of the study.

Dr. David Artis, director of the Jill Roberts Institute and the Friedman Center for Nutrition and Inflammation and the Michael Kors Professor in Immunology, and Dr. Nicholas Collins, assistant professor of immunology in medicine, both at Weill Cornell Medicine, are co-senior authors of the study.

Primary bile acids are produced by the liver and released into the gut, where diverse groups of bacteria work together to modify their chemical structures. Researchers suspected these gut microbial modifications could affect how bile acids function and interact with human signaling pathways. To test this idea, the investigators set out to explore the full extent of bacterial modifications to bile acids and understand how these changes affect their biological roles.

It turns out that gut bacteria have remarkable potential to transform bile acids. "We discovered more than fifty different bile acid molecules modified by the microbiota—many of which had never been identified before," said Dr. Guo, who is also the Halvorsen Family Research Scholar in Metabolic Health at Weill Cornell Medicine.

These newly uncovered structures could open the door to new biological insights-particularly in how they interact with human receptors that sense bile acids. Given that bile acids share the same steroid backbone as sex hormones like testosterone and estrogen, the structural resemblance raised an intriguing question for the researchers: could these microbially modified bile acids also interact with sex hormone receptors in the body? "It seemed like a wild idea at the time," Dr. Guo said.

Surprisingly, the answer appears to be yes. When the investigators tested the 56 altered bile acids that they discovered, they found one that antagonizes the androgen receptor — a molecule that interacts with sex hormones to regulate many aspects of human development. When they tested an additional 44 microbiota-modified bile acids that had previously been characterized, the team found three more that act similarly. This unexpected finding raised exciting new questions for the team: which specific cells were affected by the altered bile acids—and what biological functions these modified molecules might influence.

In addition to its role in development, the androgen receptor is also found in certain immune cells, including CD8 T cells. Previous studies have shown that blocking this receptor can enhance the ability of these immune cells to fight tumors. The investigators wondered whether the bile acids could replicate this effect by binding to and inactivating the androgen receptor. To test the idea, they treated mice with bladder cancer using these compounds—and observed a potent anti-tumor response. Further analysis revealed that the modified bile acids specifically boosted the activity of T cells—the immune cells best equipped to kill cancer.

Our results suggest that these altered bile acids help shrink tumors by enhancing T cells' ability to survive within the tumor and destroy cancer cells."

Dr. Nicholas Collins, assistant professor of immunology in medicine, Weill Cornell Medicine

"This study highlights the profound and evolving partnership between the human host and its gut microbiota, emphasizing the importance of integrating microbial activity into the design of future cancer therapies." Dr. Artis said. "It also exemplifies the power of multidisciplinary collaboration in driving microbiome science toward deeper molecular understanding of host-microbe interactions."

This discovery opens up exciting new possibilities for boosting tumor-killing immune response. Potential approaches include introducing targeted gut microbes to cancer patients before therapy, or directly administering the anti-cancer bile acids as part of treatment, the researchers suggested. Although these compounds still need to be tested in humans, the team is optimistic that bile acids could eventually become a key component of effective cancer therapies—especially when combined with existing treatments for a more powerful impact.

However, important questions remain. For example, how might diet—which is known to influence microbiota composition—affect the production of these bile acids? And beyond their anti-cancer properties, what physiological effects might these androgen receptor-blocking bile acids have in healthy individuals? The team is now focused on precisely controlling the synthesis and release of these beneficial molecules using advanced techniques to genetically engineer gut commensal bacteria, aiming to understand the broader physiological impact in the host initiated by these androgen blocking, microbiota-derived bile acids.