Gut bacteria build up common therapeutic drugs, study finds

Common drugs can build up in gut bacteria, altering bacterial function and potentially reducing the drug’s effectiveness, according to a new study. These interactions – seen for a variety of drugs, such as drugs for depression, diabetes, and asthma – could help researchers better understand individual differences in drug efficacy and side effects, the study found. published in Nature.

It is known that bacteria can chemically alter certain drugs, a process known as biotransformation. This study, conducted by researchers from the Toxicology Unit of the Medical Research Council (MRC) at the University of Cambridge and the European Molecular Biology Laboratory (EMBL) in Germany, is the first to show that certain species of intestinal bacteria accumulate human drugs, altering the types of bacteria and their activity.

This could alter the effectiveness of the drug both directly, as the build-up could reduce the availability of the drug to the body, and indirectly, as altered bacterial function and composition could be linked to side effects.

The human gut naturally contains communities of hundreds of different species of bacteria, which are important for health and disease, called the gut microbiome. The composition of bacterial species varies widely from person to person and has already been shown to be associated with a wide range of conditions, including obesity, immune response, and mental health.

In this study, the researchers cultivated 25 common gut bacteria and studied their interaction with 15 drugs taken by mouth. The drugs were chosen to represent a range of different types of common drugs, including antidepressant drugs, which are known to affect people in different ways and cause side effects such as bowel problems and weight gain.

The researchers tested how each of the 15 drugs interacted with the selected bacterial strains – a total of 375 bacterial drug tests.

They found 70 interactions between the bacteria and the drugs studied – 29 of which had not been previously reported.

While previous research has shown that bacteria can chemically modify drugs, when scientists studied these interactions more deeply, they found that for 17 of the 29 new interactions, the drug accumulated in the bacteria without being changed.

Dr Kiran Patil, from the MRC Toxicology Unit at the University of Cambridge, who co-led the study, said: “It was surprising that the majority of the new interactions that we have seen between bacteria and drugs are the drugs that accumulate in bacteria, because until now, biotransformation was considered to be the primary means by which bacteria affect the availability of drugs. “

“These will likely be very personal differences between individuals, depending on the makeup of their gut microbiota. We have seen differences even between different strains of the same species of bacteria.”

Examples of drugs that have accumulated in bacteria include the antidepressant duloxetine and the antidiabetic rosiglitazone. For some drugs, such as montelukast (an asthma medicine) and roflumilast (for chronic obstructive pulmonary disease), the two changes occurred in different bacteria – they were accumulated by certain species of bacteria and changed by others.

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

The researchers developed a small community of several bacterial species together and found that the antidepressant duloxetine drastically altered the balance of the bacterial species. The drug altered the molecules produced by the drug-accumulating bacteria, which other bacteria feed on, so that the consuming bacteria grew much larger and upset the makeup of the community.

The researchers tested the effects further using C. elegans, a nematode worm commonly used to study intestinal bacteria. They studied duloxetine, which was found to accumulate in some bacteria but not in others. In worms cultured with the bacteria species that accumulate the drug, the behavior of the worms was altered after exposure to duloxetine, compared to worms cultured with bacteria that do not accumulate duloxetine.

EMBL’s Dr Athanasios Typas, who co-led the study, said: “It is only now that people recognize that drugs and our microbiome have a mutual impact with a critical consequence on our health. . “

Dr Peer Bork, EMBL and co-lead of the study, said: “It forces us to start treating the microbiome as one of our organs.”

Dr Patil said: “The next steps for us will be to advance this basic molecular research and study how an individual’s gut bacteria relate to different individual responses to drugs such as antidepressants – the differences depending on who. you answer, the dose of medication needed, and the side effects like weight gain. If we can characterize how people react based on their microbiome makeup, then drug treatments could be individualized.

The researchers warn that the study results relate only to bacteria grown in the laboratory and that more research is needed to understand how the bioaccumulation of drugs by gut bacteria manifests inside the human body.

The study started as a collaborative project at EMBL Heidelberg and ended in Kiran Patil’s group after his move to Cambridge. It involved researchers from the Typas, Bork, Zimmermann, Hennig, Schultz and Beck groups and the EMBL Savitski team, as well as central genomics, proteomics and metabolomics facilities from EMBL Heidelberg.

This study was funded by the European Commission Horizon 2020, MRC and EMBL.

Dr Megan Dowie, MRC’s Director of Molecular and Cellular Medicine said, “This study highlights the importance of the microbiome in drug delivery, efficacy and safety. be done to understand the important molecular aspects involved here, which could lead to a positive impact on an individual’s response to a range of commonly used drugs. “

Source:

Research and innovation in the UK

Journal reference:

Klünemann, M., et al. (2021) Bioaccumulation of therapeutic drugs by human intestinal bacteria. Nature. doi.org/10.1038/s41586-021-03891-8.


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