Characterising the bidirectional biomolecular interactions between the intestinal microbiota and host drug metabolism

Marine Patricia Magali Letertre, Jonathan Swann, Ian Wilson, Imperial College London
2021
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
more » ... us 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 [...]
doi:10.25560/89730 fatcat:45smqs7z4vajzlx6jqxhtp6lj4