A groundbreaking study published in Nature Chemistry reveals how specific gut bacteria can metabolize medications targeting GPCRs (G protein-coupled receptors), potentially reducing their effectiveness. Conducted by researchers from the University of Pittsburgh and Yale University, this research examines the interaction between common oral medications and gut microbiota. With over 400 FDA-approved drugs affecting GPCRs for conditions such as migraines, depression, diabetes, and prostate cancer, understanding these interactions is crucial for personalized medicine advancements. The findings indicate that certain gut bacteria can transform these drugs into different compounds, altering their efficacy. This discovery opens new possibilities for drug design and therapeutic optimization.
Drugs targeting GPCRs are pivotal in treating various health issues. Qihao Wu, an assistant professor at the Pitt School of Pharmacy, emphasizes the importance of comprehending how these drugs interact with human gut microbiota. The study demonstrates that gut microbes can metabolize orally administered drugs, converting them into distinct chemical structures. To explore this further, Wu and his team at Yale developed a pipeline to test drug metabolism using a synthetic microbial community comprising 30 common bacterial strains found in the human gut.
In laboratory experiments, they added 127 GPCR-targeting drugs individually to tubes containing these bacteria. They then measured whether the drugs were chemically transformed and identified the resulting compounds. The results showed that out of the 127 tested drugs, 30 were metabolized by the bacterial mix, with 12 being heavily metabolized. This means that the original drug concentrations were significantly depleted due to their transformation into other compounds.
The researchers delved deeper into one heavily metabolized drug, iloperidone, used for schizophrenia and bipolar I disorder treatment. A particular bacterial strain, Morganella morganii, was found to deactivate iloperidone by transforming it into various compounds, both in lab settings and in mice. These findings suggest that specific gut bacteria could diminish the effectiveness of GPCR-targeting drugs by converting them into other substances.
Despite these promising results, Wu advises caution, stating that further research is necessary to fully understand the implications for humans. Patients should not alter or stop their medication without consulting their healthcare provider. Additionally, while the study focused on a subset of GPCR drugs, the methods employed could be applied more broadly to any orally administered chemicals. Another potential application involves investigating interactions between gut bacteria and food compounds, such as phytochemicals in corn, which may influence gut barrier function.
Moving forward, the Wu Lab aims to decode the metabolic pathways underlying these biotransformations. By doing so, strategies to enhance therapeutic efficacy and improve food and drug safety could be identified. Collaborators on this study include Deguang Song, Yanyu Zhao, Andrew Verdegaal, Tayah Turocy, and Brianna Duncan-Lowey from Yale University. This research received primary support from the National Institute of General Medical Sciences and additional funding from the National Institutes of Health.
This study underscores the intricate relationship between gut bacteria and drug metabolism. By uncovering these interactions, researchers pave the way for more effective treatments tailored to individual needs, ultimately advancing the field of personalized medicine.