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The microbiome is known to regulate many aspects of host health and disease and is increasingly being recognized as a key mediator of drug action. However, investigating the complex multidirectional relationships between drugs, the microbiota, and the host is a challenging endeavor, and the biological mechanisms that underpin these interactions are often not well understood. In this review, we outline the current evidence that supports a role for the microbiota as a contributor to both the therapeutic benefits and side effects of drugs, with a particular focus on those used to treat mental disorders, type 2 diabetes, and cancer. We also provide a snapshot of the experimental and computational tools that are currently available for the dissection of drug–microbiota–host interactions. The advancement of knowledge in this area may ultimately pave the way for the development of novel microbiota-based strategies that can be used to improve treatment outcomes.
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