Individual gut microbiota plays a significant role in drug metabolism and is a major cause of the significant variability we see in drug effectiveness between individuals.
Research has shown that there are vast differences in individual responses to drugs, recently more and more research has been published which has suggested that gut microbiota, the microbe population in our intestines, plays critical roles in this variability. (Li et al. 2015) It is estimated that although approximately one-third of our gut microbiota is common to most people, two-thirds are specific to each individual depending on factors such as age and diet. (Gut Microbiota Info, 2020) Individual variation in gut microbiota causes distinct differences in drug metabolism in the gut, therefore resulting in the numerous differences we see in responses to drug therapy. This is because most drugs are taken orally and will encounter microbes in the gut which will result in the drug molecules undergoing chemical modification, which results in products which can have different functions and side effects than the drug that they started out as.(Zimmerman et al. 2019) However, despite research showing that gut microbiota are implicated in this variability in drug response, there is still little known about the molecular mechanisms which cause these differences. The goal of this research was to determine various microbe-drug interactions through measurement of the ability of different gut bacteria to metabolize a wide range of drugs, and by doing this discover the molecular pathways behind these variations. This is important because the differences in drug response can be dangerous and expensive due to adverse side effects of the drugs as well as increased treatment length if the drug is ineffective in an individual. This research can help to address this issue by paving the way for more personalized medicine which can avoid these issues, as well as improving rational drug design more generally.
Zimmerman et al. carried out a series of experiments starting at a broad level and eventually looking at specific mechanisms by which this process could be occurring. To start they investigated the ability of 76 bacterial species, which represent the major groups of bacteria in the gut microbiome, to chemically modify a diverse range of 271 medical drugs. (Zimmerman et al. 2019) They then combined high-throughput genetics and mass spectrometry to identify drug-metabolizing microbial gene products and determine differences between these and the original drugs. (Zimmerman et al. 2019) This provided insights into the chemical and molecular processes that were happening in order to get from the original drug to the gene products. After this they developed a gain-of-function approach which determined which genes allowed for the gain of the drug metabolizing function, in order to identify gene-drug-metabolite networks which would provide insights into the mechanisms of microbiome metabolism. (Zimmerman et al. 2019) Finally, they used their gain-of-function approach to assess gene enrichment and abundance to determine if the gene products previously identified were likely to be contributing to microbial drug metabolism. (Zimmerman et al. 2019) Going from broad down to specific gene interactions allowed the researchers to get wide ranging results which each informed the next step of analysis allowing them to more specifically identify the molecular mechanisms by which these changes were occuring.
The data from these experiments produced a number of important findings. First, that the levels of two-thirds of the measured drugs were significantly reduced by at least one bacterial strain. (Zimmerman et al. 2019) This suggests gut bacteria play a significant role in drug response, providing a basis for their additional experiments. They further found that in numerous instances there was a significant mass difference between the original drug and the metabolized product, which provided the first evidence for metabolic changes in the tested drugs.(Zimmerman et al. 2019) Additionally, their developed approach resulted in gene-drug-metabolite networks which not only revealed the activity of gut microbiota but also provided insights into the molecular basis of metabolism. Finally, they found that many of the drug-metabolizing gene products showed significant enrichment, and therefore were likely contributing to the observed microbial drug metabolism. (Zimmerman et al. 2019) In addition, gene abundance was significantly correlated with the various microbe communities ability to metabolize the respective drug. These results increase the ability to explain microbial drug metabolism from genomes and potentially give the ability to predict microbiome drug metabolism.
These results provide an outline of the drug-metabolic activity of the bacteria in the gut and a mechanistic understanding of drug metabolism in the gut microbiome. This data allows us to ask if genetic testing could be done to determine those who would benefit from certain drugs and those who would suffer adverse effects. (Doestzada et al. 2018) Additionally, future research could tackle how we could manipulate individual microbiota in order to enhance drug efficacy. The answer to these questions would almost certainly result in advances in drug design and personalized medicine to improve health and most effectively treat disease.
The findings presented by Zimmerman et al. highlight the importance of personalized medicine because they show that there can never be a one size fits all treatment. Not only did they provide improved knowledge on how our gut microbe communities can impact treatment, but they also gave us the ability to eventually develop microbe-targeted approaches, and determine which drugs will be most effective for different people in order to improve medical treatment. This would allow medical treatments to not only be more efficient and safe at the individual level, but it could also cut down the cost for the patients because they would not need to try a variety of different treatments to find one that works.
Doestzada M., A.V. Vila, A. Zhernakova, et al., 2018 Pharmacomicrobiomics: a novel route toward personalized medicine?. Protein Cell. 9(5):432-445. doi: 10.1007/s13238-018-0547-2 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5960471/)
Gut Microbiota for Health by ESNM, 2020 Gut microbiota info. (https://www.gutmicrobiotaforhealth.com/about-gut-microbiota-info/)
Li H., J. He, W. Jia, 2015 The influence of gut microbiota on drug metabolism and toxicity. Expert Opinion on Drug Metabolism and Toxicology 12:1, 31-40. doi: 10.1517/17425255.2016.1121234 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5683181/)
Zimmermann M., M. Zimmermann-Kogadeeva, R. Wegmann, A.L. Goodman., 2019 Mapping human microbiome drug metabolism by gut bacteria and their genes. Nature. 570(7762):462-467. doi:10.1038/s41586-019-1291-3 (https://www.ncbi.nlm.nih.gov/pubmed/31158845)