Therapeutic Drug Accumulation in Gut Bacteria May Explain Individual Differences in Drug Response

• The availability and efficacy of therapeutic drugs can be regulated by gut bacteria.
• However, the systemic mapping of the drug-bacteria interactions has only started recently.
• The primary underlying mechanism suggested is that microorganisms chemically transform drugs in the process called biotransformation.
• Researchers investigated the reduction of 15 structurally diverse drugs by 25 representative strains of bacteria in the gut.
• The study was led by researchers from the Medical Research Council Toxicology Unit at the University of Cambridge and the European Molecular Biology Laboratory in Heidelberg, Germany.
• Researchers discovered 70 bacteria-drug interactions.
• 29 of the 70 bacteria-drug interactions had not been reported.
• More than 50 percent of the new interactions can be attributed to bioaccumulation.
• In this context, bioaccumulation occurs when bacteria store the drug intracellularly without chemically modifying it.
• Most of the time, bioaccumulation does not affect the growth of the bacteria.
• Common drugs can accumulate in gut bacteria which can alter bacterial function and reduce drug effectiveness.
• This interaction could help scientists better understand individual differences in drug responses.
• Researchers studied the molecular basis of bioaccumulation of the widely used drug called duloxetine by using click chemistry, thermal proteome profiling, and metabolomics.
• Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor antidepressant which is used to treat major depressive disorder in adults.^[2]
• Researchers found that duloxetine binds to several metabolic enzymes and affects the metabolite secretion of the respective bacteria.
• The study used defined microbial community of accumulators and non-accumulators and found that duloxetine altered the composition of the community through metabolic cross-feeding.
• Metabolic cross-feeding is defined as the interaction between bacterial strains in which molecules resulting from the metabolism of one strain are further metabolised by another strain.^[3]
• Researchers further validated their findings by using an animal model and found that bacterial bioaccumulation reduces the behavioral response of Caenorhabditis elegans to duloxetine.
• In contrast, C. elegans with bacteria that did not accumulate duloxetine showed no behavioral changes.
• C. elegans is a nematode worm commonly used to study gut bacteria.
• The results suggest that bioaccumulation by bacteria in the gut may be a common mechanism that affects drug availability and bacterial metabolism.
• Additionally, gut bacterial bioaccumulation can have an effect on microbiota composition, pharmacokinetics, side effects, and drug response, perhaps in an individual manner.

Sources:

Klünemann, M., Andrejev, S., Blasche, S., Mateus, A., Phapale, P., Devendran, S., Vappiani, J., Simon, B., Scott, T. A., Kafkia, E., Konstantinidis, D., Zirngibl, K., Mastrorilli, E., Banzhaf, M., Mackmull, M. T., Hövelmann, F., Nesme, L., Brochado, A. R., Maier, L., Bock, T., … Patil, K. R. (2021). Bioaccumulation of therapeutic drugs by human gut bacteria. Nature, 10.1038/s41586-021-03891-8. Advance online publication. https://doi.org/10.1038/s41586-021-03891-8

https://www.nature.com/articles/s41586-021-03891-8

[2] https://www.drugs.com/duloxetine.html

[3] https://www.frontiersin.org/articles/10.3389/fevo.2019.00153/full