Pharmacomicrobiomic Study Shows Significant Gut Bacteria Role in Drug Metabolism and Exposure

Featured Study: Zimmermann M, Zimmermann-Kogadeeva M, Wegmann R, Goodman AL. Mapping human microbiome drug metabolism by gut bacteria and their genes. Nature. 2019 Jun;570(7762):462-467. doi: 10.1038/s41586-019-1291-3.

There is an increasing awareness of the potential role that the gut microbiota can play in drug metabolism, drug exposure, and drug action. Orally administered drugs typically encounter gut microorganisms prior to absorption and recent studies have shown that, in some cases, these bacteria possess drug-metabolizing capabilities that can significantly influence clinical drug exposure, activity, and toxicity. Examples of such include the metabolism of omeprazole by gut anaerobes,¹ microbiota-mediated metabolism of lovastatin precipitated by antibiotic co-administration,² and the reduction of digoxin by a specific gut organism.³ This has led to the emergence of a new field of study that has strong potential to inform personalized medicine—pharmacomicrobiomics.⁴ Defined as a sub-discipline intersecting microbiology, genomics, and pharmacology, pharmacomicrobiomics studies the effects that the human microbiome has on drug exposure, activity, and toxicity. However, the field is relatively new and although there have been several reports of microbial biotransformation, there have been few in-depth investigations into the specificity of bacterial strains or the chemical determinants that may predict drug transformations.

A recent study by Zimmerman, et al. provides what may be the first in-depth examination of the molecular mechanism of biotransformation of a large number of orally administered agents by the human gut microbiota.⁵ The study surveyed the metabolic activity of 76 human gut bacteria, representing the major phyla of the human gut microbiome, against 271 oral drugs. High-throughput genetic analysis coupled with mass spectrometric methods was used to identify the bacterial gene products responsible for drug metabolism and the specific metabolic reaction. The investigators showed that after a 12-hour incubation period, two-thirds of the analyzed drugs were metabolized to a significant extent (>20%) by at least 1 of the bacterial strains investigated. They further showed that each bacterial strain that was studied metabolized between 11 and 95 drugs. Importantly, the investigators were able to identify phylum-specific metabolic activities by clustering the drug-metabolizing activities of the bacterial isolates. They reported that drugs containing ester or amide functionalities were specifically susceptible to metabolism by the Bacteroidetes, while other organisms showed a preference for nitrogen-containing functional groups.

Of key importance in this study is the investigators’ identification of specific drug-metabolizing gene products in the organisms tested. They were able to characterize 30 enzymes expressed by gut bacteria that were responsible for the metabolism of 20 drugs to 59 metabolites. This work suggests the potential for predicting drug exposure, based in part, upon genetic and microbiological analysis of a patient’s gut microbial composition and even the possibility of rationally altering a patient’s gut microflora to beneficially affect microbiome-drug interactions.

Although the field of pharmacomicrobiomics is relatively new, it is clear from recent publications that this new discipline will continue to grow. Initiatives such as the Human Microbiome Project have been started to facilitate the characterization of the human microbiota and investigate how alterations in the microbiome may affect systems pharmacology and personalized medicine.⁶ The Zimmerman, et al. study further highlights the large role that pharmacomicrobiomics will likely have in the near future, taking a place beside pharmacogenomics, metabolomics, and therapeutic drug monitoring in the personalized medicine armamentarium.

Avad is a 2^nd year professional student at University of Tennessee College of Pharmacy, enrolled in UT’s dual PharmD/PhD program. She received a Bachelor of Science degree in Chemistry from Arkansas State University.Hevener is an assistant professor of pharmaceutical sciences at University of Tennessee College of Pharmacy. His research focuses on the characterization and validation of narrow-spectrum antibacterial drug targets.

References:

1. Watanabe K, Yamashita S, Furuno K, Kawasaki H, Gomita Y. Metabolism of omeprazole by gut flora in rats. J Pharm Sci. 1995 Apr;84(4):516-7. doi: 10.1002/jps.2600840425.
2. Yoo DH, Kim IS, Van Le TK, Jung IH, Yoo HH, Kim DH. Gut microbiota‐mediated drug interactions between lovastatin and antibiotics. Drug Metab Dispos. 2014 Sep;42(9):1508-13. doi: 10.1124/dmd.114.058354.
3. Haiser HJ, Turnbaugh PJ. Developing a metagenomic view of xenobiotic metabolism. Pharmacol Res. 2013 Mar;69(1):21-31. doi: 10.1016/j.phrs.2012.07.009.
4. Sharma A, Buschmann MM, Gilbert JA. Pharmacomicrobiomics: The holy grail to variability in drug response? Clin Pharmacol Ther. 2019 Aug;106(2):317-328. doi: 10.1002/cpt.1437.
5. Zimmermann M, Zimmermann-Kogadeeva M, Wegmann R, Goodman AL. Mapping human microbiome drug metabolism by gut bacteria and their genes. Nature. 2019 Jun;570(7762):462-467. doi: 10.1038/s41586-019-1291-3.
6. ElRakaiby M, Dutilh BE, Rizkallah MR, Boleij A, Cole JN, Aziz RK. Pharmacomicrobiomics: The impact of human microbiome variations on systems pharmacology and personalized therapeutics. OMICS. 2014 Jul;18(7):402-14. doi: 10.1089/omi.2014.0018.