- A laboratory study that appears in Nature found that gut bacteria can accumulate common drugs, which may alter bacterial function and activity and decrease the effectiveness of drugs.
- The clinical significance of these findings is unknown.
- Researchers need to conduct human studies to assess and categorize drug responses based on the composition of the gut microbiome to potentially individualize and optimize drug therapy.
The human microbiome consists of 100 trillion bacteria, viruses, and fungi residing predominantly in the human gut. The microbiome plays a vital role in the:
- immunity development
- protection from harmful microorganisms
- production of short-chain fatty acids, which are a source of energy
- vitamin synthesis
- fat storage
- regulation of the central nervous system
Gut bacteria produce approximately 95% of the serotonin in the body. Serotonin is a neurotransmitter in the brain that regulates both mood and gastrointestinal (GI) functioning.
Environmental factors may induce changes to the microbiome as a response to diet, antibiotics, or disease. Nonantibiotic drugs can also alter gut microbiome composition and function.
Moreover, the gut microbiome can affect a person’s response to a drug. Gut bacteria can change the drug’s activity in the body, toxicity, or bioavailability, which is the extent and rate at which the drug enters the bloodstream.
Preliminary research in mice suggests that some antidepressants, such as duloxetine, which treat depression and anxiety by increasing serotonin and norepinephrine levels in humans, may also alter the gut microbiome. Scientists do not yet understand the effect that duloxetine has on the human microbiome.
This inspired a study, led by researchers from the Medical Research Council (MRC) Toxicology Unit at the University of Cambridge in the United Kingdom and the European Molecular Biology Laboratory in Germany, to examine the underlying mechanism behind the interactions between gut bacteria and drugs.
The scientists cultured 25 strains of common gut bacteria with a total of 15 drugs, serving three drugs as the control group, and studied their interactions in 375 different bacteria-drug paired groups. The researchers identified 29 previously unknown interactions involving 18 bacteria species and seven drugs.
Novel mechanism uncovered
Of the 29 new bacteria-drug interactions, 17 resulted from the storage of the drug by the bacteria, which scientists term bioaccumulation, and 12 from the modification of the drug by bacteria, or biotransformation.
The researchers further confirmed bioaccumulation of duloxetine in four strains of gut bacteria, using nuclear magnetic resonance and liquid chromatography with mass spectrometry.
Dr. Kiran Patil, contributing author and investigator at the MRC Toxicology Unit, elaborated in an interview with Medical News Today: “The importance of [the] relation between medications and gut bacteria has been recognized previously, but the molecular mechanisms were not fully known. Much of the focus was on whether the drug molecule is chemically modified — a process called biotransformation.”
Dr. Patil added:
“We discovered that some of the commonly used drugs, including [the] antidepressant duloxetine, are bioaccumulated by gut bacteria without chemical modification. The choice of duloxetine was due to its extensive use, previously known links to GI tract-related side effects, such as weight gain, and due to variability in response across individuals.”
The authors of the study found that duloxetine binds to metabolic enzymes in the bacteria, altering their metabolites. The researchers cultured five species of gut bacteria with duloxetine to assess whether these metabolic changes associated with bioaccumulation could cause changes to the community gut bacteria composition.
They observed that duloxetine drastically changed the composition of the bacterial community through the metabolites produced by the bacteria that accumulated duloxetine. Other bacteria fed on these metabolites, causing additional changes to the gut bacteria community.
The researchers then examined the effect of the bacteria that accumulated duloxetine versus those that did not on Caenorhabditis elegans, a nematode worm used to study gut bacteria. They found that the bacteria that accumulated duloxetine changed the behavior of the worms, compared with the non-accumulating bacteria.
Dr. Patil commented on the unexpected interactions between bacteria and drugs accumulating in the bacteria, “This not only reduced drug availability, but also the accumulated drug [changed] bacterial metabolism and the molecules they [secreted].”
Dr. Patil added: “This has a knock-on effect on other bacteria in the community. Our study thus reveals a new dimension in the microbiome-drug interactions.”
Need for human studies
When asked about the strengths and limitations of the study, Dr. Patil explained: “The biggest strength is the deep molecular insights we could obtain using state-of-the-art techniques [… to uncover] hitherto hidden dimension of bacteria-drug interactions. To gain these molecular insights, we had to limit the study to controlled laboratory conditions, and thus we cannot yet say much about [the] clinical relevance of our findings.”
Dr. Andrew Goodman, C.N.H. Long Professor of microbial pathogenesis and director of Microbial Sciences Institute at Yale School of Medicine, said in the National Institute of General Medical Sciences Biomedical Beat Blog:
“We are interested in the consequences of these host-microbiome interactions specifically in the context of medical drugs […] to understand how variation in the microbiome impacts how people respond to drugs, and we think that progress in this area would enable a lot of new health benefits.”
“For example, we could choose drugs based on a person’s microbiome composition and maybe even alter their microbiome so that they would be a better candidate for a medical drug.”
Researchers need to conduct further studies to assess the effect of the gut microbiome on drug response, and side effects in humans for these results to have a clinical impact.
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