Bile Acid Buildup Driven by Gut Dysbiosis Fuels Breast Cancer Metastasis, UVA Research Reveals
核心洞察
UVA researchers discovered that gut microbiome imbalance leads to bile acid accumulation, which triggers inflammation that promotes HR+ breast cancer metastasis, particularly to the lungs.
The study found that elevated bile acids (搜索) and insulin resistance were associated with reduced survival in human HR+ breast cancer patients.
Patients with metastatic disease who received FDA-approved bile acid sequestrants (搜索) tended to live longer, suggesting a potential repurposing opportunity.
A buildup of bile acids (搜索) caused by an unhealthy gut microbiome can drive hormone receptor-positive (HR+) breast cancer to metastasize to other parts of the body, according to new research from the University of Virginia Comprehensive Cancer Center (搜索). The findings, published in the journal Cancer Research, identify a specific mechanistic link between gut dysbiosis and breast cancer spread, opening potential avenues for prevention and improved patient outcomes.
The research, led by Melanie Rutkowski, PhD, and colleagues, demonstrates how disruption of the gut microbiome compromises the body's ability to regulate bile acid composition, creating systemic conditions that favor tumor metastasis.
"We found that an unhealthy gut microbiome loses the ability to regulate the composition of bile acids (搜索), potent signaling molecules that when not properly regulated can cause havoc on your health, metabolism and the immune system. This creates an environment throughout the body that favors breast tumor metastasis," said Rutkowski.
The Gut-Breast Cancer Axis
HR+ breast cancer represents the most common form of metastatic breast cancer, with approximately 225,000 diagnoses each year in American women. The disease tends to spread early, with tumors frequently forming in the lymph nodes and lungs. Once metastasis occurs, treatment becomes significantly more challenging and mortality risk increases.
While prior studies had established an association between gut dysbiosis and poor patient outcomes, Rutkowski's team identified the specific mechanism responsible. The study revealed that gut microbiome imbalance leads to a buildup of bile acids (搜索) — molecules that play critical roles in digestion and metabolism. This accumulation, in turn, triggers harmful breast inflammation that fuels the dissemination of breast cancer cells, particularly to the lungs.
"We found that certain bile acids (搜索) produced when the gut microbiome is disrupted can create conditions that make it easier for breast cancer cells to spread," said Audrey Putelo, PhD, co-author of the study. "Because bile acids can be measured and modified, this finding opens exciting possibilities for developing new approaches to identify high-risk patients and reduce the likelihood of metastatic disease."
Translational Evidence in Human Patients
Although the mechanistic studies were conducted in laboratory mice, the researchers extended their investigation to human patients with HR+ breast cancer. Their analysis revealed that elevated bile acids (搜索) and insulin resistance were associated with reduced survival.
Notably, patients with metastatic disease who received bile acid-suppressing medications — known as bile acid sequestrants (搜索) — tended to live longer. These drugs are already approved by the U.S. Food and Drug Administration for treating metabolic diseases, though the researchers caution that further studies are needed to establish whether the medications are directly responsible for the observed survival benefits.
"Because many of the patients who were on bile-acid sequestrants have health issues that tend to favor a worse prognosis for breast cancer, the survival of patients who were prescribed bile-acid sequestrants and who had metastatic breast cancer are extremely encouraging," Rutkowski said.
Therapeutic Implications
The findings suggest two potential therapeutic strategies: replenishing the bacteria capable of modifying bile acid composition to restore a healthy gut microbiome, or treating breast cancer patients with bile acid sequestrants (搜索). Both approaches could potentially reduce the risk of metastasis.
"Now we want to know if these existing, FDA-approved drugs can prevent the cancer from spreading in the first place. If that proves true, this could support the use of a well-tolerated class of drugs for the prevention of metastatic breast cancer," Rutkowski said.
The research was supported by the National Institutes of Health's National Cancer Institute through grants 1R01CA253285, 5R01CA262634, and P30CA044579, as well as American Cancer Society grant IRG 81-001-26. The research team consisted of Audrey M. Putelo, Simona Bajgai, Mika K. Poblete, Gabrielle Guido, Mirna Perusina Lanfranca, Qingyi He, Tajbir Raihan, Cara N. Hatzinger, Akshita Mirani, Sree H. Kolli, Daniel S. Lank, Tzu-Yu Feng, Mitchell T. McGinty, Una Miagkov, Asal Pilehvari, Wen You, Thurl E. Harris, and Melanie Rutkowski. The scientists reported no financial conflicts of interest.