Abstract
Although the importance of human genetic polymorphisms in therapeutic outcomes is well established, the role of specific genotypic or copy number variants in our "second genome" (the microbiome) has been largely overlooked. In this Perspective, I will discuss three major barriers to integrating metagenomics into pharmacology, highlighting ongoing research by us and others that has begun to shed light on the mechanisms that link the human microbiome to the efficacy and toxicity of small-molecule and biological therapies. The challenges for the next 5 years and beyond are many, requiring interdisciplinary scientific teams working at the interface of chemistry and biology, and a consideration of far more variables than traditionally included in pharmacological modeling. However, the potential benefits are immense. Continued progress could enable more precise tools for predicting patient responses and the development of a new generation of therapeutics based on, or targeted at, the human microbiome.