A new study has shown that variations in the microbiota of the human gut influence the pharmacokinetics of tamoxifen and, therefore, the efficacy of the drug. The findings, published in the American Society for Microbiology’s journal mBio, suggest that doctors might one day perform a simple test on a patient’s stool to look for specific gut bacteria that could help predict whether tamoxifen will work for her.
In the new study, researchers wanted to define the role of gut microbes in the processing of tamoxifen — that is, absorption, distribution, metabolism and excretion — because efficacy varies greatly from patient to patient. The researchers administered tamoxifen to both mice that lacked a gut microbiome and mice that had a human microbiome (which was introduced to the mice via a human stool sample). They found that mice with gut bacteria had higher levels of tamoxifen in their bloodstream. The scientists then investigated which part of the gut microbiome is responsible for controlling drug levels in the bloodstream. By examining human stool samples, they were able to identify a specific enzyme in bacteria, beta-glucuronidase, as a key factor that allows the drug to enter the bloodstream.
When a person swallows a tamoxifen pill, it travels through the stomach and into the gut, where it is absorbed into the bloodstream. In the blood, tamoxifen travels to the liver, where the drug is converted into a form that more effectively fights breast cancer. However, sometimes a sugar molecule can attach to it, signaling the body to send the cancer-fighting form of the drug back into the gut instead of into the bloodstream, where it can then travel to the parts of the body where it needs to fight cancer. This drug can leave the gut only by removing the sugar from the molecule — and the researchers found that beta-glucuronidase in gut bacteria can break down the sugar from the drug, allowing it to continue fighting breast cancer.
“Specifically, we found that certain enzymes produced by gut bacteria, called β-glucuronidase, play a role in breaking down tamoxifen. These enzymes help to shuttle tamoxifen back into the bloodstream, which can increase the drug’s efficacy,” said Alam. “We found that a specific bacterial species, Bacteroides fragilis, is strongly associated with the ability of these enzymes to positively influence tamoxifen levels in the blood. This suggests that the gut microbiome plays an important role in the action of tamoxifen in the body.”
https://journals.asm.org/doi/10.1128/mbio.01679-24
