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Drug resistant gut bacteria mimic a host mechanism for anticancer drug clearance

Peter Spanogiannopoulos, Patrick H. Bradley, Jonathan Melamed, Ysabella Noelle Amora Malig, Kathy N. Lam, Roy R. Gerona, Katherine S. Pollard, View ORCID ProfilePeter J. Turnbaugh
doi: https://doi.org/10.1101/820084
Peter Spanogiannopoulos
1Department of Microbiology & Immunology, University of California San Francisco, San Francisco, CA 94143, USA
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Patrick H. Bradley
2Gladstone Institutes, San Francisco, CA, USA
3Division of Biostatistics, Institute for Human Genetics, and Institute for Computational Health Sciences, University of California, San Francisco, CA, USA
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Jonathan Melamed
4Clinical Toxicology and Environmental Biomonitoring Laboratory, University of California, San Francisco, CA, 94143, USA
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Ysabella Noelle Amora Malig
4Clinical Toxicology and Environmental Biomonitoring Laboratory, University of California, San Francisco, CA, 94143, USA
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Kathy N. Lam
1Department of Microbiology & Immunology, University of California San Francisco, San Francisco, CA 94143, USA
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Roy R. Gerona
4Clinical Toxicology and Environmental Biomonitoring Laboratory, University of California, San Francisco, CA, 94143, USA
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Katherine S. Pollard
2Gladstone Institutes, San Francisco, CA, USA
3Division of Biostatistics, Institute for Human Genetics, and Institute for Computational Health Sciences, University of California, San Francisco, CA, USA
5Chan Zuckerberg Biohub, San Francisco, CA 94158, USA
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Peter J. Turnbaugh
1Department of Microbiology & Immunology, University of California San Francisco, San Francisco, CA 94143, USA
5Chan Zuckerberg Biohub, San Francisco, CA 94158, USA
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  • ORCID record for Peter J. Turnbaugh
  • For correspondence: Peter.Turnbaugh@ucsf.edu
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Abstract

Microbiome surveys indicate that pharmaceuticals are the top predictor of inter-individual variations in gut microbial community structure1, consistent with in vitro evidence that non-antibiotic (i.e. host-targeted) drugs inhibit gut bacterial growth2 and are subject to extensive metabolism by the gut microbiome3,4. In oncology, bacterial metabolism has been implicated in both drug efficacy5,6 and toxicity7,8; however, the degree to which bacterial sensitivity and metabolism can be driven by conserved pathways also found in mammalian cells remains poorly understood. Here, we show that anticancer fluoropyrimidine drugs broadly inhibit the growth of diverse gut bacterial strains. Media supplementation, transcriptional profiling (RNA-seq), and bacterial genetics implicated pyrimidine metabolism as a key target in bacteria, as in mammalian cells. Drug resistant bacteria metabolized 5FU to its inactive metabolite dihydrofluorouracil (DHFU) mimicking the major host pathway for drug clearance. Functional orthologs of the bacterial operon responsible (preTA) are widespread across human gut bacteria from the Firmicutes and Proteobacteria phyla. 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.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted October 25, 2019.
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Drug resistant gut bacteria mimic a host mechanism for anticancer drug clearance
Peter Spanogiannopoulos, Patrick H. Bradley, Jonathan Melamed, Ysabella Noelle Amora Malig, Kathy N. Lam, Roy R. Gerona, Katherine S. Pollard, Peter J. Turnbaugh
bioRxiv 820084; doi: https://doi.org/10.1101/820084
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Drug resistant gut bacteria mimic a host mechanism for anticancer drug clearance
Peter Spanogiannopoulos, Patrick H. Bradley, Jonathan Melamed, Ysabella Noelle Amora Malig, Kathy N. Lam, Roy R. Gerona, Katherine S. Pollard, Peter J. Turnbaugh
bioRxiv 820084; doi: https://doi.org/10.1101/820084

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