Microbiome’s Metabolism Altered by Bioaccumulation of Medications

The gut microbiome is known to play a role in modulating the availability and efficacy of therapeutic drugs. However, the work of systematically mapping bacteria-drug interactions is in its infancy. Now, new research suggests that common medications can accumulate in gut bacteria, altering bacterial function and potentially reducing the effectiveness of the drugs. These interactions—illustrated for a variety of medications, such as depression, diabetes, and asthma drugs—could help researchers to better understand individual differences in drug effectiveness and side effects.

This work is published in Nature in the paper, “Bioaccumulation of therapeutic drugs by human gut bacteria.

This study is the first to show that certain species of gut bacteria accumulate human drugs, altering the types of bacteria and their activity. This could change the effectiveness of the drug both directly, as the accumulation could reduce the availability of the drug to the body, and indirectly, as altered bacterial function and composition could be linked to side effects.

Researchers grew 25 common gut bacteria and studied how they interacted with 15 drugs that are taken orally. The drugs were chosen to represent a range of different types of common drugs. The researchers tested how each of the 15 drugs interacted with the selected bacterial strains—a total of 375 bacteria-drug tests. They found 70 interactions between the bacteria and the drugs studied—of which 29 had not been previously reported.

While earlier research has shown bacteria can chemically modify drugs—a process known as biotransformation—when the scientists studied these interactions further, they found that for 17 of the 29 new interactions, the drug accumulated within the bacteria without being modified.

“It was surprising that the majority of the new interactions we saw between bacteria and drugs were the drugs accumulating in the bacteria, because up until now biotransformation was thought to be the main way that bacteria affect the availability of drugs,” noted Kiran R. Patil, PhD, group leader at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany. “These will likely be very personal differences between individuals, depending on the composition of their gut microbiota. We saw differences even between different strains of the same species of bacteria.”

Examples of drugs that accumulated in bacteria include the antidepressant duloxetine and the anti-diabetic rosiglitazone. For some drugs, such as montelukast (an asthma drug) and roflumilast (for chronic obstructive pulmonary disease), both changes happened in different bacteria—they were accumulated by some species of bacteria and modified by others.

They also found the bioaccumulation of drugs alters the metabolism of the accumulating bacteria. For example, the antidepressant drug duloxetine bound to several metabolic enzymes within the bacteria and altered their secreted metabolites.

The researchers grew a small community of several bacterial species together and found the antidepressant duloxetine dramatically altered the balance of bacterial species. The drug altered the molecules produced by the drug-accumulating bacteria, which other bacteria feed on, so the consuming bacteria grew much more and unbalanced the community composition.

When C. elegans were grown with the bacteria that had been shown to accumulate duloxetine, the behavior of the worms was altered after being exposed to the drug, compared with worms that were grown with bacteria that did not accumulate duloxetine.

“Next steps for us will be to take forward this basic molecular research and investigate how an individual’s gut bacteria tie with the differing individual responses to drugs such as antidepressants—differences in whether you respond, the drug dose needed, and side effects like weight gain,” noted Patil. “If we can characterize how people respond depending on the composition of their microbiome, then drug treatments could be individualized.”

The researchers caution that the study findings are only on bacteria grown in the lab and more research is needed to understand how bioaccumulation of medications by gut bacteria manifests inside the human body.

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