Abstract
The microbiome plays a key role in health and disease, and there has been considerable interest in therapeutic targeting of the microbiome as well as mining this rich resource in drug discovery efforts. However, a growing body of evidence suggests that the gut microbiota can itself influence the actions of a range of xenobiotics, in both beneficial and potentially harmful ways. Traditionally, clinical studies evaluating the pharmacokinetics of new drugs have mostly ignored the important direct and indirect effects of the gut microbiome on drug metabolism and efficacy. Despite some important observations from xenobiotic metabolism in general, there is only an incomplete understanding of the scope of influence of the microbiome specifically on drug metabolism and absorption, and how this might influence systemic concentrations of parent compounds and toxic metabolites. The significance of both microbial metabolism of xenobiotics and the impact of the gut microbiome on host hepatic enzyme systems is nonetheless gaining traction and presents a further challenge in drug discovery efforts, with implications for improving treatment outcomes or counteracting adverse drug reactions. Microbial factors must now be considered when determining drug pharmacokinetics and the impact that an evolving and dynamic microbiome could have in this regard. In this review, we aim to integrate the contribution of the gut microbiome in health and disease to xenobiotic metabolism focusing on therapeutic interventions, pharmacological drug action, and chemical biotransformations that collectively will have implications for the future practice of precision medicine.
Highlights
The principles of xenobiotic metabolism, which is defined as the metabolism of ingested exogenous molecules, emphasize the role of the liver as the predominant site of biotransformation after ingestion by the host
We aim to integrate the contribution of the gut microbiome in health and disease to xenobiotic metabolism focusing on therapeutic interventions, pharmacological drug action, and chemical biotransformations that collectively will have implications for the future practice of precision medicine
This is considered within the context of our expanding knowledge of the role played by the gut microbiota in health and disease, host–microbial interactions, and the reciprocal relationship between xenobiotics and the gut bacteria involved in their metabolism
Summary
The principles of xenobiotic metabolism, which is defined as the metabolism of ingested exogenous molecules, emphasize the role of the liver as the predominant site of biotransformation after ingestion by the host. The collective direct and indirect metabolic influence of these microbes in the gastrointestinal tract is evaluated with regard to the chemical modification of pharmaceutical compounds, dietary components, and environmental agents, and the implications for host health. This is considered within the context of our expanding knowledge of the role played by the gut microbiota in health and disease, host–microbial interactions, and the reciprocal relationship between xenobiotics and the gut bacteria involved in their metabolism. We discuss the potential therapeutic implications arising from these observations before providing recommendations to guide a currently neglected but growing area of research toward therapeutic dividends and the improvement of human health
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