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

Peter Spanogiannopoulos, Than S. Kyaw, Ben G. H. Guthrie, Patrick H. Bradley, Joyce V. Lee, Jonathan Melamed, Ysabella Noelle Amora Malig, Kathy N. Lam, Daryll Gempis, Moriah Sandy, Wes Kidder, Erin L. Van Blarigan, Chloe E. Atreya, Alan Venook, Roy R. Gerona, Andrei Goga, 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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Than S. Kyaw
1Department of Microbiology & Immunology, University of California San Francisco, San Francisco, CA 94143, USA
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Ben G. H. Guthrie
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 94158, USA
3Department of Microbiology, The Ohio State University, Columbus, OH 43210, USA
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Joyce V. Lee
4Department of Cell & Tissue Biology, University of California San Francisco, San Francisco, CA 94143, USA
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Jonathan Melamed
5Clinical Toxicology and Environmental Biomonitoring Laboratory, University of California, San Francisco, CA, 94115, USA
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Ysabella Noelle Amora Malig
5Clinical Toxicology and Environmental Biomonitoring Laboratory, University of California, San Francisco, CA, 94115, 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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Daryll Gempis
1Department of Microbiology & Immunology, University of California San Francisco, San Francisco, CA 94143, USA
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Moriah Sandy
6Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
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Wes Kidder
6Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
7UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA
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Erin L. Van Blarigan
7UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA
8Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA, 94158, USA
9Department of Urology, University of California, San Francisco, San Francisco, CA 94158, USA
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Chloe E. Atreya
6Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
7UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA
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Alan Venook
6Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
7UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA
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Roy R. Gerona
5Clinical Toxicology and Environmental Biomonitoring Laboratory, University of California, San Francisco, CA, 94115, USA
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Andrei Goga
4Department of Cell & Tissue Biology, University of California San Francisco, San Francisco, CA 94143, USA
7UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA
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Katherine S. Pollard
2Gladstone Institutes, San Francisco, CA 94158, USA
8Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA, 94158, USA
10Institute for Human Genetics, University of California, San Francisco, CA 94143, USA
11Bakar Computational Health Sciences Institute, University of California, San Francisco, CA 94143, USA
12Chan 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
12Chan 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

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 microbiome3,4. In oncology, bacterial metabolism has been implicated in both drug efficacy5,6 and toxicity7,8; 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.

Competing Interest Statement

P.J.T. is on the scientific advisory boards for Pendulum, Seed, and SNIPRbiome; there is no direct overlap between the current study and these consulting duties. K.S.P. is on the scientific advisory board for Phylagen; there is no direct overlap between the current study and these consulting duties. C.E.A serves on the scientific advisory board for Pionyr Immunotherapeutics and has received research funding (institution) from Bristol Meyer Squibb, Guardant Health, Kura Oncology, Merck, and Novartis; there is no direct overlap with the current study. All other authors have no relevant declarations.

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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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A conserved enzyme found in diverse human gut bacteria interferes with anticancer drug efficacy
Peter Spanogiannopoulos, Than S. Kyaw, Ben G. H. Guthrie, Patrick H. Bradley, Joyce V. Lee, Jonathan Melamed, Ysabella Noelle Amora Malig, Kathy N. Lam, Daryll Gempis, Moriah Sandy, Wes Kidder, Erin L. Van Blarigan, Chloe E. Atreya, Alan Venook, Roy R. Gerona, Andrei Goga, Katherine S. Pollard, Peter J. Turnbaugh
bioRxiv 820084; doi: https://doi.org/10.1101/820084
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A conserved enzyme found in diverse human gut bacteria interferes with anticancer drug efficacy
Peter Spanogiannopoulos, Than S. Kyaw, Ben G. H. Guthrie, Patrick H. Bradley, Joyce V. Lee, Jonathan Melamed, Ysabella Noelle Amora Malig, Kathy N. Lam, Daryll Gempis, Moriah Sandy, Wes Kidder, Erin L. Van Blarigan, Chloe E. Atreya, Alan Venook, Roy R. Gerona, Andrei Goga, Katherine S. Pollard, Peter J. Turnbaugh
bioRxiv 820084; doi: https://doi.org/10.1101/820084

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