Gut microbiome-xenobiotic interactions: focus on drug metabolism

The fate and activity of drugs are frequently dictated not only by the host per se but also by the microorganisms present in the gastrointestinal tract. While the ever-increasing scientific breakthroughs have highlighted the influence of the gut microbiome on health and well-being, mechanistic insights on the role of the microbiota on the metabolism of orally administered therapeutics and endogenous signalling molecules remain relatively understudied. However, a growing body of evidence now suggests the gut microbiome can itself influence the actions of a range of drugs. This functional metabolic repertoire includes the capacity for drug activation, reactivation and detoxification by bacterial-derived enzymes, the consequences of which can be either beneficial or potentially harmful on the host. More recently, the ability of the microbiome to indirectly influence host metabolism has been suggested, but there remains only a rudimentary understanding of the molecular underpinnings and potential implications of this effect. Moreover, no study has extensively investigated the impact of the gut microbiome on drug efflux transporters. The overarching goal of this thesis was to further investigate gut microbiome-drug interactions by addressing some key outstanding questions in how it, both directly and indirectly, metabolises drugs and more specifically, what impact perturbations to its function or composition has on drug pharmacokinetics. To achieve this goal, in Chapter 2, an ex vivo metabolism assay, fecalase, was characterised to identify drugs susceptible to direct metabolism by bacterial-derived enzymes. Given variability in drug-metabolising enzymes can be a crucial source of inter-individual variability in drug response, we examined whether host related factors, including sex, age and genetics, can influence the drug-metabolising capacity of the gut microbiota while in Chapter 3, the primary objective was to explore the influence of perturbations of the gut microbiome on the drug-metabolising and transport capacity of the host. Fuelled by our findings illuminating the effects of microbiota-targeted interventions on metabolism by both the gut microbiota and host, we took a more integrated in vivo approach in Chapter 4 to enhance the understanding of how such manipulations may affect the pharmacokinetics of neuroactive drugs. Cumulatively, the results reveal that perturbations to the gut microbiome can introduce variability in both faecal enzymatic activity and the expression of host genes implicated in drug metabolism and transport. Moreover, the pharmacokinetic results draw attention to the capacity of the gut microbiome to alter the systemic concentrations of specific drugs. Finally, limitations of the fecalase model for assessment of bacterial-mediated drug metabolism using current approaches have been identified, and suggestions for future optimisation have been made. Successful exploitation of these prominent but neglected features of the gut microbiome has the potential to inform personalised medicine, and targeted nutritional approaches. To this end, this work has provided the impetus to identify mechanisms driving reciprocal drug-gut microbiota interactions, to guide the development of microbiome-targeted dietary or pharmacological interventions, with the potential to enhance drug efficacy or reduce drug side-effects