It is a well-known fact that a broad range of drugs can affect gut microbiota composition. Furthermore, the gut microbiome may affect drug efficacy and toxicity—previous findings have suggested that gut microbes could shape benefits from cancer immunotherapy—thus contributing to the explanation of why not all patients respond in the same way to the same medication. However, little is known about the quantitative contribution of the host and the gut microbiome to drug metabolism.
A new study, led by Dr. Andrew Goodman from the Yale University School of Medicine (New Haven, USA), provides some clues about how the gut microbiome influences the host’s ability to metabolize medical drugs by using an experimental and computational methodology.
The researchers studied, both in vitro and in vivo, the effects of gut bacteria on the metabolism of two antiviral drugs—brivudine and sorivudine—and of benzodiazepine clonazepam.
The in vitro incubation of both human and murine liver fractions and fecal microbiota with the oral antiviral drug brivudine revealed that both liver and microbial enzymes are involved in the enzymatic transformation of brivudine (BRV) into the toxic metabolite bromovinyluracil (BVU). After oral BRV administration, conventional mice accumulated increased levels of the toxic metabolite BVU not only in their serum, but also in cecum, feces and liver, when compared with genetically identical mice without microbiota. These findings suggest a relevant contribution by the gut microbiome, along with host enzymes, to BRV metabolism.
Bacteroides thetaiotaomicron and B. ovatus, commonly found in the mammalian gut microbiota, exhibited the highest level of BRV metabolism activity and the authors identified the responsible microbiome-encoded enzyme that was rate-limiting for BRV metabolism. Experiments with germ-free mice colonized with wild-type B. thetaiotaomicron and germ-free mice colonized with mutant B. thetaiotaomicron without the microbial drug-metabolizing enzyme confirmed the indispensable role of this bacterial gene in BRV metabolism. Without this gene, the bacterium can no longer break down the drug.
In a second step, the researchers administered oral BRV and quantified drug and metabolite kinetics in different body compartments in mice over time. After the drug entered the body, it could either be absorbed into the bloodstream and metabolized by the liver, or it remain in the intestines where it was metabolized by the gut microbiota. Mice carrying bacteria engineered to lack in BRU-transforming ability exhibited much less BRV absorption in the intestine, increased BRV excretion in feces and decreased BVU accumulation in the liver, when compared with mice colonized with wild-type B. thetaiotaomicron.
With the help of mathematical models, the researchers sought to quantify the contribution of host and gut microbiota to systemic drug and metabolite exposure. The physiologically-based model of host and microbial contribution to BRV and BVU pharmacokinetics took into account variables such as BRV absorption from the small and large intestines, BRV elimination, host BRV to BVU conversion, BVU elimination and intestinal transit.
Zimmermann and colleagues found that gut bacteria contributed up to 70% of serum BVU in germ-free mice colonized with B. thetaiotaomicron wild-type, as well as in conventional mice that harbor a complex microbiota. It is worth mentioning that chemical parameters of the drugs, physiological parameters of the host and microbial drug metabolism rate can all significantly affect the estimated microbial contribution to drug pharmacokinetics.
In order to explore the general nature of these findings, the researchers also studied how gut bacteria contribute to the metabolism of two other drugs: antiviral drug sorivudine and anti-anxiety drug clonazepam. It was discovered that gut bacteria play a considerable role in circulating toxic metabolites derived from these drugs. In the case of clonazepam, the microbiota contributes up to 78% of the circulating aminoclonazepam, whereas it contributes up to 66% of aminohydroxyclonazepam, which is a metabolite generated by both microbial and host enzymes.
In conclusion, the host gut microbiota is an important contributor to circulating toxic metabolites of certain drugs such as antivirals brivudine and sorivudine and anti-anxiety drug clonazapem. These findings are a step forward in understanding which drugs should be given to a patient in order to minimize their toxic side effects and also opens up the option of manipulating the gut microbiome to achieve an enhanced therapeutic response.
Zimmermann M, Zimmermann-Kogadeeva M, Wegmann R, et al. Separating host and microbiome contributions to drug pharmacokinetics and toxicity. Science. 363:eaat9931. doi: 10.1126/science.aat9931.