A conserved enzyme found in diverse human gut bacteria interferes with anticancer drug efficacy

Abstract

Pharmaceuticals are the top predictor of inter-individual variations in gut microbial community structure¹, consistent with in vitro evidence that host-targeted drugs inhibit gut bacterial growth² and are extensively metabolized by the gut microbiome^3,4. In oncology, bacterial metabolism has been implicated in both drug efficacy^5,6 and toxicity^7,8; however, the degree to which bacterial drug sensitivity and metabolism can be driven by conserved pathways also found in mammalian cells remains poorly understood. Here, we show that anticancer fluoropyrimidine drugs inhibit the growth of diverse gut bacterial strains by disrupting pyrimidine metabolism, as in mammalian cells. Select bacteria metabolized 5-fluorouracil (5-FU) to its inactive metabolite dihydrofluorouracil (DHFU), mimicking the major host pathway for drug clearance. The preTA operon was necessary and sufficient for 5-FU inactivation in Escherichia coli, exhibited high catalytic efficiency for the reductive reaction, decreased the bioavailability and efficacy of oral fluoropyrimidine treatment in mice, and was prevalent in the gut microbiomes of colorectal cancer patients prior to and during treatment. The observed conservation of both the targets and pathways for metabolism of therapeutics across domains highlights the need to distinguish the relative contributions of human and microbial cells to drug disposition⁹, efficacy, and side effect profiles.