Breaking down the microbiology world one bite at a time
Your gut bacteria are little drug depots.
By now you are probably aware that therapeutic drugs can (negatively) affect our gut microbiome. But are you aware that our gut microbiome can affect both the availability and efficacy of therapeutic drugs? You read that correctly, bacteria-drug interaction is a two-way street. The main mechanism by which bacteria influence drug availability is via biotransformation, or the chemical transformation of drugs by microorganisms. In 2019, a study reported that over one hundred drug molecules were chemically transformed by our gut bacteria. This process has different outcomes depending on the bacteria and the drug. For example, lovastatin and sulfasalazine are transformed into their active forms, but the opposite is true for digoxin. Despite the increasing evidence of the effect on drug activity and efficacy, as well as microbial fitness, the systematic mapping of these drug-bacteria interactions only recently began.
Bioaccumulation by gut bacteria…
Aiming to expand our knowledge on this topic, Klümann et al. profiled the interactions between 15 (12 + 3 controls) human-targeted drugs and 25 representative strains of human gut bacteria (figure 1).
Figure 1. Schematic representation of the experimental set-up for profiling of bacteria-drug interaction. Image created by author with BioRender.com based on method description in Klünemann, M., Andrejev, S., Blasche, S. et al. Bioaccumulation of therapeutic drugs by human gut bacteria. Nature 597, 533–538 (2021). https://doi.org/10.1038/s41586-021-03891-8
The resulting 375 bacteria-drug pairs revealed 70 bacteria-drug interactions, including 29 which had not been reported before (figure 2). Interestingly, 17 of these 29 newly identified interactions turned out to be bioaccumulation events, or storage of the drug by bacteria without modifying it, rather than biotransformation events. In addition, the study showed that biotransformation and -accumulation interactions were not mutually exclusive.
Figure 2. Bacteria-drug interaction network identified in study. Left network: biotransformation or bioaccumulation of drugs by gut bacteria. Right network: the effect of drugs on the growth of gut bacteria. Image credits: Klünemann, M., Andrejev, S., Blasche, S. et al. Bioaccumulation of therapeutic drugs by human gut bacteria. Nature 597, 533–538 (2021). https://doi.org/10.1038/s41586-021-03891-8
The mechanism behind drug biotransformation is conceivable (hint: metabolic enzymes), but what about drug bioaccumulation? To investigate the molecular basis of drug accumulation, Klümann et al. studied the protein targets of duloxetine in different bioaccumulating gut bacterial strains. Using techniques such as click chemistry pull down and thermal proteome profiling (TPP), they found several enzymatic proteins that structurally responded to duloxetine. In addition to the identification of target proteins, the researchers also showed that the binding of duloxetine to these bacterial metabolic enzymes altered the metabolism of the bioaccumulating strains (figure 3). Thus, bioaccumulation not only impacts the bioavailability of the drug, but also modifies the cellular physiology of drug-accumulating bacteria!
Figure 3. Left: schematic representation of metabolic changes by bioaccumulation. A small-molecule drug such as duloxetine structurally binds a bacterial ‘target’ protein, which affects the function of the latter. Right: Nucleotide biosynthetic pathway (i.e. important bacterial metabolic pathway) in bioaccumulating C. saccharolyticummarking the duloxetine-binding (click-chemistry pull down assay, blue) or -responding (TPP assay, orange) enzymes. Differentially secreted metabolites (i.e. measure for altered metabolism) are underlined. Image created in BioRender.com; nucleotide synthetic pathway copied from Klünemann, M., Andrejev, S., Blasche, S. et al. Bioaccumulation of therapeutic drugs by human gut bacteria. Nature 597, 533–538 (2021). https://doi.org/10.1038/s41586-021-03891-8
…and its consequences.
Metabolic interactions play a fundamental role in shaping the composition of gut microbial communities. This begs the question whether the metabolic changes associated with bioaccumulation also affect the community composition. Klümann et al. addressed this by assembling stable communities consisting of five gut bacterial species, including a duloxetine bioaccumulator (Streptococcus salivarius) and a species that is directly inhibited by duloxetine (Eubacterium rectale). They found that the presence of duloxetine noticeably changed the community composition, resulting in a 100-fold increase in abundance of E. rectale (figure 4). Although duloxetine bioaccumulation by S. salivarius may confer a protective effect on E. rectale, the bacterium’s increase in the presence of the drug would require growth-promoting interactions. Here, Klümann et al. showed that the duloxetine-mediated changed metabolite secretion by S. salivarius boosted E. rectale growth, allowing the bacteria to bloom (figure 5). Thus, human-targeted drugs can modulate gut microbial communities 1) through direct inhibition of certain community members, and 2) through modification of the metabolic interactions between bacteria in a community.
Figure 4. duloxetine bioaccumulation alters the community composition. Image credits: Klünemann, M., Andrejev, S., Blasche, S. et al. Bioaccumulation of therapeutic drugs by human gut bacteria. Nature 597, 533–538 (2021). https://doi.org/10.1038/s41586-021-03891-8.
Figure 5. Bioaccumulation of duloxetine by S. salivarius causes E. rectale to bloom. Image created by author with BioRender.com based on Klünemann, M., Andrejev, S., Blasche, S. et al. Bioaccumulation of therapeutic drugs by human gut bacteria. Nature 597, 533–538 (2021). https://doi.org/10.1038/s41586-021-03891-8
Lastly, how does bioaccumulation affect the host-drug response? To investigate this, Klümann et al. looked at the response of C. elegans to duloxetine bioaccumulation. Since duloxetine regulates behaviour (muscular movement), the researchers used animal movement as readout. Their experiment showed that the presence of duloxetine-bioaccumulating strains affected the host response by attenuating the therapeutic effect of duloxetine (duloxetine slows movements; bioaccumulation of duloxetine in microbes → decreased availability to host target cells → less effect → more movements observed).
In conclusion, Klüman et al. uncovered two ways in which bioaccumulation by gut bacteria can alter the therapeutic effect of host-targeted drugs: 1) reduced drug availability, and 2) changed bacterial metabolite secretion. This changed metabolite secretion can lead to changes in the community composition, which is associated with side-effects, and potentially interferes with the mode of action of some drugs. Thus, mapping these reciprocal drug-bacteria interactions can help us better predict alterations in drug availability and bacterial metabolism, as well as the implications for microbiota composition, pharmacokinetics, side-effects and host-drug responses.
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Image created by author with BioRender.com