25The human gut microbiome harbors hundreds of bacterial species with 26 diverse biochemical capabilities, making it one of nature's highest density, 27 highest diversity bioreactors. Several drugs have been previously shown to be 28 directly metabolized by the gut microbiome, but the extent of this phenomenon 29 has not been systematically explored. Here, we develop a systematic screen for 30 mapping the ability of the complex human gut microbiome to biochemically 31 transform small molecules (MDM-Screen), and apply it to a library of 575 clinically 32 used oral drugs. We show that 13% of the analyzed drugs, spanning 28 33 pharmacological classes, are metabolized by a single microbiome sample. In a 34 proof-of-principle example, we show that microbiome-derived metabolism occurs 35 in vivo, identify the genes responsible for it, and provide a possible link between 36 its consequences and clinically observed features of drug bioavailability and 37 toxicity. Our findings reveal a previously underappreciated role for the gut 38 microbiome in drug metabolism, and provide a comprehensive framework for 39 characterizing this important class of drug-microbiome interactions. 40 41 42 43 44 45 46 47iii) a defined mouse colonization assay for assessing the effect of the microbiome on the 94 pharmacokinetics of selected drugs. Using MDM-Screen with 575 clinically used, orally 95 administered, small molecule drugs, we discovered that 13% of them can be subject to 96 MDM. As a proof-of-principle example, we selected one of these transformations -97 MDM deglycosylation of fluoropyrimidines -for further functional investigations. We 98 identify microbiome-derived species and enzymes responsible for this transformation, 99show that it occurs in vivo in a microbiome-dependent manner, and provide evidence 100 that its consequences may explain outcomes already observed in the clinic. Our screen 101 described here, and the findings obtained from it represent the first systematic map of 102 microbiome-derived metabolism of clinically used drugs, and provide a framework for 103incorporating an "MDM" module in future drug development pipelines.