Researchers have found that gut bacteria can interfere with the effectiveness of over 400 commonly used medications that target GPCRs, cellular receptors involved in treating conditions like depression, migraines, and diabetes.
These microbes can break down drugs in the digestive system, potentially making them less effective. The discovery adds a new layer to how we understand personalized medicine and drug response, suggesting the gut microbiome could play a key role in whether a treatment works or not.
How Gut Bacteria Affect Drug Effectiveness
A new study published today (April 3) in Nature Chemistry by researchers from the University of Pittsburgh and Yale University reveals that common gut bacteria can metabolize certain oral medications, potentially reducing their effectiveness. These drugs target GPCRs, short for G protein-coupled receptors, a large group of cellular receptors involved in many biological processes.
More than 400 GPCR-targeting medications have been approved by the U.S. Food and Drug Administration (FDA) to treat a wide range of conditions, including migraines, depression, type 2 diabetes, and prostate cancer.
Personalized Medicine Meets the Microbiome
“Understanding how GPCR-targeted drugs interact with human gut microbiota is critical for advancing personalized medicine initiatives,” said first author Qihao Wu, Ph.D., assistant professor in the Pitt School of Pharmacy, who started this project as a postdoctoral researcher at Yale. “This research could help open up new avenues for drug design and therapeutic optimization to ensure that treatments work better and safer for every individual.”
While drug responses vary based on factors like age, genetics, and diet, recent research has shown that gut microbes also play a key role. These microbes can chemically alter drugs after they’re ingested, potentially changing how well the drugs work.
Testing Drug Reactions with Synthetic Microbial Communities
To learn more about which gut bacteria metabolize which drugs, Wu and the team at Yale, including the labs of Jason Crawford, Ph.D., Noah Palm, Ph.D., and Andrew Goodman, Ph.D., built a pipeline to rapidly and efficiently test this in the lab. They started by building a synthetic microbial community composed of 30 common bacterial strains found in the human gut. To tubes containing the bacteria, they added each of 127 GPCR-targeting drugs individually. Then they measured whether these drugs were chemically transformed and, if so, which compounds were produced.
30 Drugs Affected, With 12 Heavily Transformed
The experiment showed that the bacterial mix metabolized 30 of the 127 tested drugs, 12 of which were heavily metabolized, meaning that concentrations of the original drug were greatly depleted because they were transformed into other compounds.
Next, the researchers looked more closely at one heavily metabolized drug called iloperidone, which is often used to treat schizophrenia and bipolar I disorder. One bacterial strain in particular, Morganella morganii, inactivated iloperidone by transforming it a range of different compounds, both in the lab and in mice.
Gut Bacteria’s Potential to Inactivate Medications
Overall, the findings suggest that specific gut bacteria could make GPCR-targeting drugs less effective by transforming them into other compounds.
However, Wu cautioned that more research is needed to understand potential impacts in people and that patients shouldn’t stop taking or change their medication without consulting their provider.
Beyond GPCRs: Food Compounds and Broader Applications
Although the study focused on a subset of GPCR drugs, the approaches could be applied more broadly to any orally administered chemicals, according to Wu.
“Another potential application of this pipeline is investigating interactions between gut bacteria and compounds found in food,” he said. “For example, we identified a couple of phytochemicals in corn that may affect gut barrier function. Notably, we observed that the gut microbiome could potentially protect us from these phytochemicals by detoxifying them.”
Next Steps: Mapping the Microbial Metabolism
The next goal of the Wu Lab is to decode the metabolic pathway underlying these biotransformations, which could potentially identify strategies for improving therapeutic efficacy and enhancing food and drug safety.
Reference: “Activity of GPCR-targeted drugs influenced by human gut microbiota metabolism” by Qihao Wu, Deguang Song, Yanyu Zhao, Andrew A. Verdegaal, Tayah Turocy, Brianna Duncan-Lowey, Andrew L. Goodman, Noah W. Palm and Jason M. Crawford, 3 April 2025, Nature Chemistry.
DOI: 10.1038/s41557-025-01789-w
Other authors on the study were Deguang Song, Ph.D., Yanyu Zhao, Andrew Verdegaal, Ph.D., Tayah Turocy, Ph.D., and Brianna Duncan-Lowey, Ph.D., all of Yale University.
This research was primarily supported by the National Institute of General Medical Sciences (1RM1GM141649). It was also supported by the National Institutes of Health (DP2DK125119 and R01AT010014).
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