Characterising the bidirectional biomolecular interactions between the intestinal microbiota and host drug metabolism
Creators: name: Letertre, Marine Patricia Magali
Publisher: name: Imperial College London
Year: 2019

description: In pharmacological and toxicological studies, the aim is to improve drug efficacy while limiting toxicity. It is now recognised that the gut microbiota, which constitutes trillions of microbial cells and contains 150 time more genes that the human genome itself, can synthesise enzymes and metabolites that can influence the metabolism and toxicity of drugs in the host. Conversely, drugs themselves have also been identified to exert an impact on the community structure of the gut microbiota and thus modify its overall functionality. Such bidirectional interactions can have implications for host health and the outcomes of treatment strategies and therefore, it is essential that these complex events are further understood. In this work a combination of metataxonomic and metabolomic approaches have been used to explore various drug-microbiota-host interactions. Firstly, a common chemotherapeutic, methotrexate, was studied. When administrated to rats at different doses, this drug was found to have a dose-dependent effect on the faecal microbial profile of the animals. Conversely, colonic bacteria in these animals were found to express an enzyme that was able to detoxify methotrexate by converting it into the non-toxic metabolite, 2,4-diamino-N-10-methylpteroic acid (DAMPA). Bacteria belonging to the phylum Firmicutes were found to correlate with this detoxification process suggesting that measuring this bacterial group (or their enzymes) prior to treatment with methotrexate could be used to prevent high dose MTX-induced toxicity. Being able to systematically investigate the capacity of an individual’s microbiome to directly metabolize a specific drug could help to inform treatment strategies to maximise efficacy and minimise toxicity. To achieve this, an in vitro model was developed to monitor the concentration of a drug following its incubation with faecal samples from different human donors. Despite technical limitations and the need for further development, this work demonstrated the potential utility of this model for rapidly monitoring the drug degradation capacity of an individual’s microbiome. The potential for the gut microbiome to indirectly modulate the drug metabolism of the host was then explored in mice. Here, a high-tyrosine diet was fed to mice to increase the microbial production of p-cresol in the presence and absence of antibiotics. This work furthered our understanding of the influence of gut-derived p-cresol on the sulfation capacity of the host liver and its effect on the phase II drug metabolism of paracetamol. Finally, the benefits of inhibiting a specific bacterial enzyme implicated in the toxicity of irinotecan was explored to improve the outcomes of this drug. The metabolic perturbations induced by the inhibitor were found to be restricted to the gut environment with minimal biochemical consequences for the host. This demonstrates that selective inhibition of gut microbial enzymes could be an attractive target to complement the development of future drugs. These investigations highlight the importance of taking into consideration the gut microbiota in clinical, pharmaceutical and toxicological studies. The gut microbiota can explain a notable proportion of toxicity and variability in drug responses and evaluating an individual’s gut microbiota prior to drug treatment could help to improve drug outcomes. As technology advances and costs reduce, there is increasing potential to measure and use this microbial metric in the clinical setting to facilitate the implementation of stratified and personalised medicine.