Could Your Gut Microbiome Make Certain Drugs Less Effective?
Gut bacteria have been shown to metabolize certain GPCR-targeting drugs and may render them less effective.
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The effectiveness of a drug can vary among individuals, influenced by factors like age, genetics and diet. These variant drug responses can have significant ramifications for patients, such as a lack of clinical improvement and dangerous adverse reactions. The gut microbiome has emerged as an important player in research looking to better understand variations in drug metabolism.
A new study, published in Nature Chemistry, shows how common gut bacteria can metabolize certain oral medications that target cellular receptors, potentially reducing the drug's effectiveness.
“In some cases, the benefits of certain medications take time to appear and can vary a lot from person to person, especially when it comes to long-term effectiveness and side effects. While many factors contribute to these differences, such as genetics and diet, we believe that gut bacteria also play a key role,” Dr. Qihao Wu, assistant professor at the University of Pittsburgh, told Technology Networks. “These microbes can chemically modify drugs, which may affect how well the drugs work.”
The researchers believe that understanding how drugs interact with the human gut microbiome is critical for advancing personalized medicine and hope that these findings could help open new avenues for drug design.
Gut bacteria influence GPCR drug metabolism
In the study, Wu and team used a community of 30 bacterial strains commonly found in the human gut. They then added 127 G-protein-coupled receptor (GPCR)-targeting drugs individually to the microbial community and measured whether the drugs were metabolized and, if so, which compounds were produced.
G-protein-coupled receptors (GPCRs)
GPCRs are a large family of cell surface receptors that act as a bridge between external chemical information (such as hormones) and intracellular signaling pathways. They play a role in a vast array of cellular processes and have been associated with several disease pathways, including various neurodegenerative and psychiatric diseases.
There are currently over 400 US Food and Drug Administration (FDA) approved drugs targeting more than 100 GPCRs and many more remain under development or in clinical trials. Understanding the factors that impact the efficacy of GPCR-targeted drugs is, therefore, of great clinical importance.
“Testing all 400+ GPCR drugs for microbial metabolism isn’t practical, so we chose 127 representative GPCR drugs based on their key chemical structures. These selected drugs reflect most of the diversity found in the full set,” explained Wu.
Performing metabolomics studies, the researchers observed that 30 of the 127 were metabolized by the microbial community, with 12 being robustly metabolized (defined as drugs that were consumed at a level higher than 80%).
As a next step, the researchers further investigated one of the drugs that were robustly metabolized, called iloperidone, an antagonist at multiple receptors, including dopamine receptor D2 that is often used to treat schizophrenia and bipolar I disorder.
“We discovered that a particular bacterial strain, Morganella morganii, can break down the drug iloperidone into several different compounds. This finding suggests that there may be more drug-breakdown products than we observed in past studies,” said Wu.
“As for what this means for people taking iloperidone, it could help scientists better understand how the drug is processed in the gut. That said, our findings are still at the research stage and were observed in a lab setting. Until more is known, patients should not make any changes to their medication without consulting their healthcare provider.”
Discussing whether any of the drugs were metabolized into potentially harmful substances, Wu explained, “It's possible that some of the drugs could turn into harmful substances once they're broken down by the gut microbes, but right now we don't have enough evidence to say for certain. This is something my lab is really interested in studying in the future: to better understand whether these changes might be helpful or harmful to the body.”
Beyond GPCR-targeting drugs, Wu and colleagues believe this approach could be applied to study other orally consumed compounds: “This includes different classes of drugs, nutrients such as amino acids, chemicals found in food, pollutants that might be accidentally consumed and even naturally occurring substances produced by the human body,” Wu said. “We're especially interested in how gut microbes can chemically modify these compounds and how those changes might affect both the human body and the microbes themselves.”
These findings highlight the significant impact gut microbes can have on drug metabolism, emphasizing the importance of considering individual gut microbiomes when developing personalized medicines. “Our next steps involve identifying the specific enzymes in gut bacteria responsible for these changes. We hope that by targeting these microbial enzymes, we can improve how consistently and effectively medications work for different people,” Wu concluded.
Reference: Wu Q, Song D, Zhao Y, et al. Activity of GPCR-targeted drugs influenced by human gut microbiota metabolism. Nat Chem. 2025. doi: 10.1038/s41557-025-01789-w
About the interviewee
Dr. Qihao Wu, assistant professor at the University of Pittsburgh. Credit: University of Pittsburgh School of Pharmacy.
Dr. Qihao Wu joined the Department of Pharmaceutical Sciences at the University of Pittsburgh as an assistant professor in February 2025. The Wu Lab explores two major research areas. The first focuses on gut microbial metabolism of xenobiotics, aiming to unravel how the gut microbiome metabolizes xenobiotics, including drugs and dietary compounds and its broader implications for human health. The second area centers on paired omics-directed natural product discovery, utilizing omics technologies to uncover the untapped potential of orphan biosynthetic gene clusters from marine and human microbial symbionts for small-molecule drug discovery and development.
Wu earned his PhD in medicinal chemistry as a joint-training graduate student at Zhejiang University of Technology and the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, under the guidance of Dr. Hong Wang and Dr. Yue-Wei Guo.
