The importance of the human gut microbiome has been repeatedly emphasized in these GEITP pages. With regard to gene-environment interactions, each animal (including humans) is different — with regard to genetics, epigenetic factors, endogenous influences (e.g. heart and kidney diseases), environmental effects, and contributions from their microbiome — and this will affect interindividual response to drugs. Understanding how an individual patient will respond to a given drug is, of course, important in developing plans for the optimal treatment (’personalized medicine’).
Authors [see attached article & editorial] have taken this field one step further, by an exhaustive study of human intestinal bacteria and how drugs are naturally metabolized by these bacteria. The earliest example of a drug being metabolized by bacteria — was described in the 1930s: Prontosil, the first widely-used antibiotic, was shown in mice that it was metabolized by Streptococcus pyogenes; it was later established that prontosil is metabolized by gut bacteria to form sulfanilamide, the active form of the drug (interestingly, had prontosil been tested for activity against S. pyogenes in a test tube, as we do today, its capacity to generate an antibiotic would have been overlooked). Other examples of gut bacteria affecting drug metabolism include microbial inactivation of digoxin (used for heart conditions), and modification of the chemotherapeutic agent irinotecan, thereby leading to toxic side effects.
Authors [see attached] conducted microbial cell culture tests to assess the ability of 76 bacterial strains from the human gut — representing 68 species from main bacterial taxonomic groupings — to metabolize 271 drugs (selected to provide a diverse group in terms of factors — such as molecular structure or effect on the body). Collectively, these microorganisms encode ~150-fold more genes than the human genome; this genetic diversity comprises a rich enzyme reppository, having enormous drug-metabolizing potential. Authors established that these drug-metabolizing microbial proteins can contribute to the in vivo drug metabolism of gnotobiotic mice (i.e. an environment in which all microorganisms are either known or excluded). Authors incubated each gut species or strain with each drug pool and three vehicle controls under anaerobic conditions (i.e. no O2), and, via liquid-chromatography-coupled mass spectrometry (LC–MS), measured drug concentrations before, and after, a 12-h incubation. The 3,840 samples analyzed comprise a total of 20,596 bacteria–drug interactions, measured in quadruplicate. Wow.
These combined high-throughput analyses (genetics plus mass spectrometry) systematically identified microbial gene products that metabolize drugs. These microbiome-encoded enzymes can directly — and substantially — affect intestinal and systemic drug metabolism in mice. Authors suggest their data might help explain drug-metabolizing activities of human gut bacteria, and communities, on the basis of the bacterial genomic contents. These causal links between gene content and metabolic activities of the microbiota connect interpersonal (and inter-ethnic) variability in microbiomes to interindividual differences in drug metabolism. Obviously, these findings have important implications for medical therapy and drug development across multiple disease indications. 😊
DwN
Nature 27 June 2o19; 570: 462-467 & News’N’Views pp 453-454