The impact that the microbiome has on drug metabolism is further elucidated in new research showing for the first time that bacteria in the gut accumulate and store drug compounds.

That could have a two-pronged effect, both reducing the effectiveness of a drug by limiting its availability, and sparking side effects linked to altered bacterial function and composition.

The research adds to the growing understanding of the profound effect the gut microbiome has on drug metabolism. It is now time to start treating the microbiome as an organ in its own right, said coauthor of the research, Kiran Patil, who is an investigator at the MRC Toxicology Unit at Cambridge University.

"There is now sufficient evidence, including from our study, to warrant considering microbiome-drug interactions in drug development," Patil said. "It is likely that many inter-individual differences in drug response and side effects are linked to the microbiome, and thus considering the potential drug-bacteria interactions will benefit precision medicine," he told BioWorld Science.

In the study, published in Nature on September 8, 2021, the researchers cultured 25 common gut bacteria and looked at how they interacted with 15 orally administered drugs.

Of a total of 375 bacteria/drug tests, they observed 70 interactions, of which 29 have not previously been reported.

Up to this point it was thought the main impact of gut bacteria on drugs was through biotransformation, in which compounds are directly chemically modified by bacteria.

But for 17 of the 29 new observed interactions, the drug accumulated intracellularly within the bacteria without being modified. In most cases, the growth of the bacteria was not affected.

"Bioaccumulation of host-targeted drugs has not been reported before to our knowledge. We show that this has consequences for bacterial metabolism, due to drug binding to metabolic enzymes, and consequently on inter-bacteria metabolic interactions," said Patil.

"There [are] of course implications for drug availability. Together, there are fundamental implications for microbiome dynamics as well as individual drug response and toxicity," he said.

While there is growing acceptance of the fundamental role of gut microbiota in drug efficacy, mode of action and side effects, the specific interactions are not known for the vast majority of drugs.

Given this, these findings of novel drug/host interactions should be investigated further in animal models and in humans, the researchers say. In addition, the potential significance for drug effectiveness in and between individuals, calls for an attempt to systematically map the interactions between drugs and gut microorganisms.

"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 drug," said Patil.

"These will likely be very personal differences between individuals, depending on the composition of their gut microbiota," Patil said. "We saw differences even between different strains of the same species of bacteria."

The bacterial species assessed were selected to cover a broad phylogenetic and metabolic diversity, representative of a health gut microbiome, while the 12 orally administered drugs were selected to span diverse chemistry, indications and known side effect profiles.

Among the drugs that were shown to bioaccumulate, the antidepressant Cymbalta (duloxetine hydrochloride) and the diabetes treatment Avandia (rosiglitazone maleate), were exclusively bioaccumulated, each in a different number of bacteria species.

However, for some drugs, bioaccumulation and biotransformation went hand-in-hand, with the asthma treatment Singulair (montelukast sodium) and the chronic obstructive pulmonary disease therapy Daliresp (roflumilast) bioaccumulated by some bacteria and degraded by others.

Of the bacteria tested, all strains except Fusobacterium nucleatum were both biotransformers and bioaccumulators.

Bacterial community

Investigating the implications of this, in further research it was shown that by altering the metabolites generated by bioaccumulating bacteria, which in turn are metabolized by other bacteria, Cymbalta dramatically altered the composition of the bacterial community.

To investigate the molecular mechanisms behind bioaccumulation of small molecules that are not designed to target microorganisms, the researchers looked for protein targets of Cymbalta in bioaccumulating bacteria.

The screen showed Cymbalta binds to metabolic enzymes, promoting intracellular storage of the drug. The binding altered the metabolites that were secreted.

"We know that the drug is intracellular and binds to many metabolic enzymes," said Patil. "Changes in bacterial metabolism is one of the main impacts, as we observed in terms of altered secretion of metabolites. We show that this altered secretion can change community composition, by creating new cross-feeding opportunities in a bacterial community."

The possible effects of these alterations were assessed using a Caenorhabditis elegans model of gut bacteria. In worms cultured with species of bacteria that had been shown to bioaccumulate Cymbalta, the muscular movements of C. elegans were altered after being exposed to the antidepressant, compared to worms grown with bacteria that did not bioaccumulate the drug.

"It's clear that further work needs to be done to understand the important molecular aspects involved here," said Megan Dowie, head of molecular and cellular medicine at the MRC toxicology unit. "This study highlights the importance of the microbiome in drug delivery, effectiveness and safety," she said.

The next step will be to take forward the basic molecular research and investigate how individual gut microbiomes related to differences seen in the response to drugs, Patil said. For Cymbalta, these differences could range from side effects such as weight gain, to the dose required to have an effect, to the fundamental question of whether a particular individual will respond to the drug at all.

"We would like to study how the molecular mechanisms that we identified manifest in the host context - so we will establish collaborations with clinical scientists with a special focus on antidepressants," said Patil.

"If we can characterize how people respond depending on the composition of their microbiome, then drug treatments could be individualized," he said.