Evidence (not surprising) to show that gut bacteria do metabolize drugs

There was a time (not long ago) that many pharmacologists were insisting that the DNA sequence of one, or just a few, genes would be able to predict that patient’s response to a drug; or, to many drugs. Then came the Human Genome Project (starting in Oct 1990), followed by the realization that the human genome has many single-nucleotide variants (SNVs) –– also called single-nucleotide polymorphisms (SNPs) in the late 1990s –– and this was followed by whole-genome association studies (GWAS, starting about 2oo6) using hundreds of thousands or a million or more SNPs, and now we have whole-exome sequencing (WES) and whole-genome sequencing (WGS) of dozens or hundreds of individuals.

During these transitions, it has become increasingly clear that DNA sequence alone will virtually never determine an individual’s genetic predispoition to a particular drug. Besides DNA sequence (the genome) we have epigenetic effects and environmental effects that will influence the genetic risk prediction. Environmental effects include diet, medical conditions, taking multiple drugs, lifestyle and occupation, etc. Another factor that will contribute to “noise” in trying to predict an individual patient’s drug response is described here: the gut bacteria (microbiome) normally living in each person’s gastrointestinal tract (and specific to each individual, and also varying over time) –– will also contribute to genetic prediction of drug response.

Fluoropyrimidines are the first-line treatment for colorectal cancers, but their efficacy is highly variable between patients. Authors [see attached article] asked whether gut microbes (a known source of interindividual variability) would have an impact on drug efficacy. Combining two tractable genetic models, the bacterium E. coli and the nematode (flatworm) C. elegans, authors carried out three-way high-throughput screens that unraveled the complexity underlying host-microbe-drug interactions. They found that microbes can enhance, or suppress, the effects of fluoropyrimidines through metabolic drug intercon version involving bacterial vitamins B6, B9, and ribonucleotide metabolism. Also, disturbances in bacterial deoxynucleotide pools amplify 5-FU-induced autophagy (self-cannibalism) and cell death in host cells, an effect regulated by the bacterial nucleoside diphosphate kinase, ndk-1.

These data suggest a two-way bacterial mediation of fluoropyrimidine effects on host metabolism, which contributes to drug efficacy. These findings highlight the potential therapeutic power of manipulating one’s intestinal microbiota to ensure host metabolic health –– and perhaps for treating cancer in mammals, including patients with cancer receiving fluoropyrimidine chemotherapy.

Cell 2o17; 169: 442–456

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