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.
- 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.
- 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.
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