Reports looking at the metabolism of drugs by microorganisms in the intestine date back in 1974. Since then, the bacterial metabolic capacity in drug degradation, known as biotransformation, has gained significant scientific interest. Research has primarily focused on the positive potentials of biotransformation, yet the metabolite’s behavior has been major concern in the field; is it more or less active than the parent compound?
With the latter question driving drug-gut microbiome research for years, the accidentally found role of metformin (described in 2015), first-line drug for type 2 diabetes, in shaping gut microbiota alterations to a greater extent than the disease itself was quite surprising. As Prof. Dr. Peer Bork described earlier, this finding raised two questions around the role of gut microbiome in (a) the drug intake-associated side-effects, and (b) the mode of drugs’ action.
Therefore, research groups in European Molecular Biology Laboratory (EMBL) teamed up and developed in vitro platforms to map the effects of numerous drugs on human gut commensals.
In a new study, scientists from EMBL and the University of Cambridge made use of this platform and revealed that common medications–from antidepressants to antidiabetic drugs–can accumulate in gut bacteria altering bacterial function and potentially reducing medications effectiveness.
The authors grew 25 representative bacterial strains of the healthy human gut microbiota and tested their interactions with 15 commonly used drugs that are taken orally. The resulting 375 drug-bacteria pairs were cultured in the aforedescribed in vitro platforms that allowed for anaerobic conditions in order to resemble the human gut lumen. They found 70 interactions between the gut bacteria and the drugs studied, of which 29 had not been previously reported.
Depletion of the drug was measured after 48 hours of anaerobic growth in both culture supernatants and extracts of the total culture, where bacterial cells were also included. Interestingly, when the authors compared the drug concentrations in the two conditions, they came across 17 drug-bacteria cases in which the drug was depleted in the supernatant but could be recovered from the total culture. This implied an accumulation of the drugs in the bacterial cells beyond the increasingly classical scenario of chemical transformation by the bacterial enzymes.
Kiran Patil, outgoing EMBL Group Leader, now based at the Toxicology Unit at the University of Cambridge, who co-led the study, said: “It was surprising that the majority of the new interactions we saw between bacteria and drugs were the drugs accumulating in the bacteria, because up until now biotransformation was thought to be the main way that bacteria affect the availability of drugs.”
Of note, duloxetine, a widely used antidepressant, was bioaccumulated by eight bacterial species, ergo the authors chose it as a drug of interest to further unravel the challenging molecular basis of drug bioaccumulation by gut bacteria. They found that its bioaccumulation actually alters the metabolism of the accumulating bacteria by binding to several metabolic enzymes and changing their metabolite secretion. Previous research in mice showed species-specific effects of the gut microbiota in mediating the antidepressant effect of duloxetine.
Considering that metabolic interactions are fundamental in shaping the composition of gut microbial communities, the authors went one step further and challenged the stability of a distinct five-taxa microbial community. The presence of duloxetine markedly shifted the community composition by creating cross-feeding opportunities; duloxetine altered the molecules produced by the drug-accumulating bacteria, which other bacteria feed on, so the consuming bacteria grew much more and unbalanced the community composition.
As a last step, the authors explored the effect of duloxetine bioaccumulation on host response. Nematode worms, often used to study host-microbe interactions, were chosen as model system and animals movement was examined as behavioral readout. In the presence of bioaccumulating strains, worms behavior was altered after being exposed to duloxetine, that was not the case when worms were grown with bacteria that did not accumulate duloxetine.
The latter made the authors suggest further investigation on the microbiome-duloxetine-host interaction in other model systems or in a clinical setting.
It is indeed quite recently that researchers dived into the pharmacist inside us and attempted to explore the implications of drug-gut microbiome interactions outside of the usual box of biotransformation.
On the whole, the authors reveal that commonly used non-antibiotic drugs accumulate in commensal bacteria of the healthy human gut microbiota and may therefore alter gut microbial functions, potentially reducing medication’s effectiveness.
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Forslund K., Hildebrand F., Nielsen T. et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota Nature. 2015; 528: 262–266 doi: 10.1038/nature15766
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human gut bacteria Nature. 2021; 597: 533–538 doi:10.1038/s41586-021-03891-8
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