Gut bacteria can reduce the effectiveness of common medications

Gut bacteria can reduce the effectiveness of common medications

A new study published todayNatural chemistryFrom researchers at the University of Pittsburgh and Yale University shows how common gut bacteria can metabolize certain oral medications that target cellular receptors called GPCRS, potentially making these important drugs less effective.

Drugs that act on GPCRs, or G protein-coupled receptors, include more than 400 drugs approved by the U.S. Food and Drug Administration (FDA) to treat many common medical conditions such as migraines, depression, type 2 diabetes, prostate cancer, and more.

“Understanding how GPCR-targeted drugs interact with human gut microbiota is critical to advancing personalized medicine initiatives,” said first author Qihao Wu, Ph.D., an assistant professor at the Pitt School of Pharmacy, who started this project as a postdoctoral researcher at Yale. “This research could help open new avenues for drug design and therapeutic optimization to ensure treatments work better and safer for each individual.”

The effectiveness of a drug varies from person to person, influenced by age, genetic makeup, diet and other factors. More recently, researchers found that microbes in the gut can also metabolize orally administered drugs, breaking these compounds down into different chemical structures and potentially altering their effectiveness.

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. They began by building a synthetic microbial community consisting of 30 common strains of bacteria found in the human gut. They added 127 GPCR-targeting drugs individually to tubes containing the bacteria. They then measured whether these drugs were chemically transformed and, if so, what compounds were produced.

The experiment showed that the bacterial mixture metabolized 30 of the 127 drugs tested, 12 of which were heavily metabolized, meaning that the concentrations of the original drug were severely depleted because they were converted into other compounds.

Next, the researchers examined a highly metabolized drug called ilooperidone, which is often used to treat schizophrenia and bipolar I disorder. In particular, a bacterial strainMorganella morganii,Inactivated ilooperidone by transforming a range of different compounds, both in the laboratory and in mice.

Overall, the results suggest that specific gut bacteria could make GPCR-targeting drugs less effective by converting them into other compounds.

But Wu cautioned that more research is needed to understand potential effects on people and that patients should not stop taking or change their medications without consulting their provider.

Although the study focused on a subset of GPCR drugs, WU says the approaches could be applied more broadly to orally administered chemicals.

Another potential application of this pipeline is to study the interactions between gut bacteria and compounds in food. For example, we have identified a few phytochemical forces in corn that may influence intestinal barrier function. Remarkably, we observed that the gut microbiome could potentially protect us from these phytochemical foods by detoxifying them. “

Qihao Wu, Ph.D., assistant professor, Pitt School of Pharmacy

The WU lab's next goal is to decipher the metabolic pathway underlying these biotransformations, which could potentially identify strategies to improve therapeutic efficacy and improve food and drug safety.

Additional authors of the study were Deguang Song, Ph.D., Yanyu Zhao, Andrew Verdigaal, 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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