Researchers at Princeton University have developed a way of systematically evaluating how the microbial communities in our intestines can chemically transform, or metabolize, drugs that are taken orally, in ways that impact on their efficacy and potentially safety. The new methodology—which the team used to evaluate the gut microbiome’s effect on hundreds of common medications already on the market—provides a more complete picture of how gut bacteria metabolize drugs. The framework could also feasibly help in the development of drugs that are more effective, have fewer side effects, and are personalized to an individual’s microbiome.

Previous studies have examined how single species of gut bacteria can metabolize oral medications, but the new framework enables evaluation of a person’s entire intestinal microbial community. “Basically, we do not run and hide from the complexity of the microbiome, but instead, we embrace it,” said Mohamed S. Donia, PhD, assistant professor of molecular biology. “This approach allows us to gain a holistic and more realistic view of the microbiome’s contribution to drug metabolism.”

Donia and colleagues reported on their findings in Cell, in a paper titled, “Personalized Mapping of Drug Metabolism by the Human Gut Microbiome.”

Most drugs are taken orally, and they are then absorbed in the small or large intestine, from where they can reach the circulation, the authors explained. The microbiome that colonizes the human gut system contains hundreds of bacterial species that encode an estimated 100 times more genes than the human genome. Prior studies have shown how dozens of drugs are metabolized by individual gut microbiome species but, as the authors pointed out, the enormous diversity and richness of the complete microbiome represents “ … a repertoire of yet-uncharacterized biochemical activities capable of metabolizing ingested chemicals.” As they further pointed out, “ … the extent of this phenomenon is rarely explored in the context of microbial communities.”

Donia commented, “This inter-person variability underscores why studying a single bacterial species makes it impossible to compare the microbiome’s metabolism of drugs between individuals. We need to study the entire intestinal microbial community.” To try and address this in more detail the Princeton investigators developed a quantitative method for mapping what they have termed the microbiome-derived metabolism (MDM) of orally administered drugs, using gut microbiome-derived microbial communities from different people. They explained, “In the current study, we developed a quantitative experimental workflow for assessing the ability of the human gut microbiome to directly metabolize orally administered drugs, using a combination of microbial community cultivation, small-molecule structural analysis, quantitative metabolomics, functional genomics and metagenomics, and mouse colonization assays.”

The researchers collected 21 fecal samples from anonymous donors and cataloged the bacterial species living in each individual. They found that the donors each had a unique gut microbial community, and that the majority of these personalized communities could be grown in a lab culturing system.

They then tested 575 FDA-approved drugs against just one of the cultured microbiomes to see which of the drugs was chemically modified. Then they tested a much smaller subset of the drugs against all of the cultured microbiomes. The results identified microbiome-derived metabolites that had never been previously reported, as well as metabolites that had been reported in humans and associated with side effects, but that were of unknown origin. The findings also highlighted cases where all the donor microbiomes performed the same reactions on the drug, and others where only a subset did.

The results indicated that some people’s microbiomes had little effect on a given drug, while other microbiomes had a significant effect. This demonstrated how important the community of bacteria—rather than just single species—is on drug metabolism. “Everyone’s microbiome is unique, and we were able to see this in our study,” said Bahar Javdan, an MD-PhD student in molecular biology and a co-first author on the study. “We observed three main categories—drugs that were consistently metabolized by all the microbiomes in our study, drugs that were metabolized by some and not by others, and drugs that were not subject to any microbiome-derived metabolism.”

The results highlighted how use of the framework could reveal unknown drug-microbiome interactions. Overall, there were 57 cases in which gut bacteria altered existing oral medications. “Of the successfully analyzed drugs, we identified 57 (13%) as MDM+,” the team noted. “These spanned 28 pharmacological classes and even more based on their chemical structure … Of these 57, 80% had not been previously reported.”

Researchers at Princeton created a system for evaluating how the body’s gut bacteria alter the safety and efficacy of everyday drugs. The system can be used in pharmaceutical research to improve drug discovery and development. [Janie Kim. Published in Cell.]

The alterations ranged from converting the drug into an inactive state—which could reduce its efficacy—to converting the drug into a form that is toxic, potentially causing side effects. The team said that the ability to screen much larger numbers of drugs against multiple donor-derived microbiomes will likely highlight an even greater amount of microbiome-related impact on medications. “A simultaneous expansion into hundreds of drugs and hundreds of donor samples is necessary to reveal the complete biochemical potential of MDM: it is very likely that the types of MDM transformations observed here are an underestimation of all possible ones,” they wrote.

As part of their studies, the scientists also examined the mechanisms by which some of the modified drugs were altered by the cultured microbiomes. To understand exactly how the transformations occurred, they traced the source of the chemical transformations to particular bacterial species and to genes within those bacteria. They also showed that microbiome-derived metabolic reactions discoverable using their approach could be recapitulated in a mouse model, which is the first step in adapting the approach for human drug development.

The framework could feasibly be used to aid drug discovery by identifying potential drug-microbiome interactions early in development, and so inform on formulation changes. It could also be used during clinical trials to better analyze drug toxicity and efficacy, and be harnessed to help personalize treatment to the microbiome of each patient. This could help to predict how a certain drug will behave, and suggest changes to the therapeutic strategy if undesired effects are predicted. “Our framework identifies novel drug-microbiome interactions that vary between individuals and demonstrates how the gut microbiome might be used in drug development and personalized medicine,” the team concluded.

“This is a case where medicine and ecology collide,” said Jaime Lopez, a graduate student in the Lewis-Sigler Institute for Integrative Genomics and a co-first author on the study, who contributed the computational and quantitative analysis of the data. “The bacteria in these microbial communities help each other survive, and they influence each other’s enzymatic profiles. This is something you would never capture if you didn’t study it in a community.”

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