Connecting the dots: Targeting the microbiome in drug toxicity

The gut microbiota has a vast influence on human health and its role in initiating, aggravating, or ameliorating diseases is beginning to emerge. Recently, its contribution to heterogeneous toxicological responses is also gaining attention, especially in drug-induced toxicity. Whether they are orally administered or not, drugs may interact with the gut microbiota directly or indirectly, which leads to altered toxicity. Present studies focus more on the unidirectional influence of how xenobiotics disturb intestinal microbial composition and functions, and thus induce altered homeostasis. However, interactions between the gut microbiota and xenobiotics are bidirectional and the impact of the gut microbiota on xenobiotics, especially on drugs, should not be neglected. Thus, in this review, we focus on how the gut microbiota modulates drug toxicity by highlighting the microbiome, microbial enzyme, and microbial metabolites. We connect the dots between drugs, the microbiome, microbial enzymes or metabolites, drug metabolites, and host toxicological responses to facilitate the discovery of microbial targets and mechanisms associated with drug toxicity. Besides this, current mainstream strategies to manipulate drug toxicity by targeting the microbiome are summarized and discussed. The review provides technical reference for the evaluation of medicinal properties in the research and development of innovative drugs, and for the future exploitation of strategies to reduce drug toxicity by targeting the microbiome.