Research Highlights: Therapeutic Drug Accumulation in Gut Bacteria May Explain Individual Differences in Drug Response


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

September 12, 2021

  • 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