Host and gut bacteria share metabolic pathways for anti-cancer drug metabolism

Pharmaceuticals have extensive reciprocal interactions with the microbiome, but whether bacterial drug sensitivity and metabolism is driven by pathways conserved in host cells remains unclear. Here we show that anti-cancer fluoropyrimidine drugs inhibit the growth of gut bacterial strains from 6 phy...

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Published inNature microbiology Vol. 7; no. 10; pp. 1605 - 1620
Main Authors Spanogiannopoulos, Peter, Kyaw, Than S., Guthrie, Ben G. H., Bradley, Patrick H., Lee, Joyce V., Melamed, Jonathan, Malig, Ysabella Noelle Amora, Lam, Kathy N., Gempis, Daryll, Sandy, Moriah, Kidder, Wesley, Van Blarigan, Erin L., Atreya, Chloe E., Venook, Alan, Gerona, Roy R., Goga, Andrei, Pollard, Katherine S., Turnbaugh, Peter J.
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 01.10.2022
Nature Publishing Group
Subjects
38
38/91
45/23
5-Fluorouracil
631/326/2565/2134
631/67/70
64/60
692/4017
82
82/58
Animals
Antibacterial activity
Antineoplastic Agents - metabolism
Antineoplastic Agents - pharmacology
Antitumor agents
Bacteria - genetics
Bioavailability
Biomedical and Life Sciences
Cancer
Colorectal carcinoma
Drug metabolism
Escherichia coli
Escherichia coli - genetics
Escherichia coli - metabolism
Fluorouracil - metabolism
Fluorouracil - pharmacology
Humans
Infectious Diseases
Intestinal microflora
Life Sciences
Mammalian cells
Mammals
Medical Microbiology
Metabolic Networks and Pathways
Metabolic pathways
Metabolism
Metabolites
Mice
Microbiology
Microbiomes
Parasitology
Virology
Online AccessGet full text
ISSN2058-5276
2058-5276
DOI10.1038/s41564-022-01226-5

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Abstract Pharmaceuticals have extensive reciprocal interactions with the microbiome, but whether bacterial drug sensitivity and metabolism is driven by pathways conserved in host cells remains unclear. Here we show that anti-cancer fluoropyrimidine drugs inhibit the growth of gut bacterial strains from 6 phyla. In both Escherichia coli and mammalian cells, fluoropyrimidines disrupt pyrimidine metabolism. Proteobacteria and Firmicutes metabolized 5-fluorouracil to its inactive metabolite dihydrofluorouracil, mimicking the major host mechanism for drug clearance. The preTA operon was necessary and sufficient for 5-fluorouracil inactivation by E. 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. The conservation of both the targets and enzymes for metabolism of therapeutics across domains highlights the need to distinguish the relative contributions of human and microbial cells to drug efficacy and side-effect profiles. Anti-cancer fluoropyrimidine drugs have antibacterial effects on the gut microbiome, and these drugs can be metabolized by gut bacteria via conserved pathways also found in mammalian hosts.
AbstractList Pharmaceuticals have extensive reciprocal interactions with the microbiome, but whether bacterial drug sensitivity and metabolism is driven by pathways conserved in host cells remains unclear. Here we show that anti-cancer fluoropyrimidine drugs inhibit the growth of gut bacterial strains from 6 phyla. In both Escherichia coli and mammalian cells, fluoropyrimidines disrupt pyrimidine metabolism. Proteobacteria and Firmicutes metabolized 5-fluorouracil to its inactive metabolite dihydrofluorouracil, mimicking the major host mechanism for drug clearance. The preTA operon was necessary and sufficient for 5-fluorouracil inactivation by E. 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. The conservation of both the targets and enzymes for metabolism of therapeutics across domains highlights the need to distinguish the relative contributions of human and microbial cells to drug efficacy and side-effect profiles.
Pharmaceuticals have extensive reciprocal interactions with the microbiome, but whether bacterial drug sensitivity and metabolism is driven by pathways conserved in host cells remains unclear. Here we show that anti-cancer fluoropyrimidine drugs inhibit the growth of gut bacterial strains from 6 phyla. In both Escherichia coli and mammalian cells, fluoropyrimidines disrupt pyrimidine metabolism. Proteobacteria and Firmicutes metabolized 5-fluorouracil to its inactive metabolite dihydrofluorouracil, mimicking the major host mechanism for drug clearance. The preTA operon was necessary and sufficient for 5-fluorouracil inactivation by E. 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. The conservation of both the targets and enzymes for metabolism of therapeutics across domains highlights the need to distinguish the relative contributions of human and microbial cells to drug efficacy and side-effect profiles.Pharmaceuticals have extensive reciprocal interactions with the microbiome, but whether bacterial drug sensitivity and metabolism is driven by pathways conserved in host cells remains unclear. Here we show that anti-cancer fluoropyrimidine drugs inhibit the growth of gut bacterial strains from 6 phyla. In both Escherichia coli and mammalian cells, fluoropyrimidines disrupt pyrimidine metabolism. Proteobacteria and Firmicutes metabolized 5-fluorouracil to its inactive metabolite dihydrofluorouracil, mimicking the major host mechanism for drug clearance. The preTA operon was necessary and sufficient for 5-fluorouracil inactivation by E. 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. The conservation of both the targets and enzymes for metabolism of therapeutics across domains highlights the need to distinguish the relative contributions of human and microbial cells to drug efficacy and side-effect profiles.
Pharmaceuticals have extensive reciprocal interactions with the microbiome, but whether bacterial drug sensitivity and metabolism is driven by pathways conserved in host cells remains unclear. Here we show that anti-cancer fluoropyrimidine drugs inhibit the growth of gut bacterial strains from 6 phyla. In both Escherichia coli and mammalian cells, fluoropyrimidines disrupt pyrimidine metabolism. Proteobacteria and Firmicutes metabolized 5-fluorouracil to its inactive metabolite dihydrofluorouracil, mimicking the major host mechanism for drug clearance. The preTA operon was necessary and sufficient for 5-fluorouracil inactivation by E. 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. The conservation of both the targets and enzymes for metabolism of therapeutics across domains highlights the need to distinguish the relative contributions of human and microbial cells to drug efficacy and side-effect profiles.Anti-cancer fluoropyrimidine drugs have antibacterial effects on the gut microbiome, and these drugs can be metabolized by gut bacteria via conserved pathways also found in mammalian hosts.
Pharmaceuticals have extensive reciprocal interactions with the microbiome, but whether bacterial drug sensitivity and metabolism are driven by pathways conserved in host cells remains unclear. Here, we show that anti-cancer fluoropyrimidine drugs inhibit the growth of gut bacterial strains from 6 phyla. In both Escherichia coli and mammalian cells, fluoropyrimidines disrupt pyrimidine metabolism. Proteobacteria and Firmicutes metabolized 5-fluorouracil (5-FU) to its inactive metabolite dihydrofluorouracil (DHFU), mimicking the major host mechanism for drug clearance. The preTA operon was necessary and sufficient for 5-FU inactivation by E. 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. The conservation of both the targets and enzymes for metabolism of therapeutics across domains highlights the need to distinguish the relative contributions of human and microbial cells to drug efficacy and side effect profiles. Anti-cancer fluoropyrimidine drugs have anti-bacterial effects on the gut microbiome and these drugs can be metabolized by gut bacteria via conserved pathways also found in mammalian hosts.
Pharmaceuticals have extensive reciprocal interactions with the microbiome, but whether bacterial drug sensitivity and metabolism is driven by pathways conserved in host cells remains unclear. Here we show that anti-cancer fluoropyrimidine drugs inhibit the growth of gut bacterial strains from 6 phyla. In both Escherichia coli and mammalian cells, fluoropyrimidines disrupt pyrimidine metabolism. Proteobacteria and Firmicutes metabolized 5-fluorouracil to its inactive metabolite dihydrofluorouracil, mimicking the major host mechanism for drug clearance. The preTA operon was necessary and sufficient for 5-fluorouracil inactivation by E. 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. The conservation of both the targets and enzymes for metabolism of therapeutics across domains highlights the need to distinguish the relative contributions of human and microbial cells to drug efficacy and side-effect profiles. Anti-cancer fluoropyrimidine drugs have antibacterial effects on the gut microbiome, and these drugs can be metabolized by gut bacteria via conserved pathways also found in mammalian hosts.
Author Guthrie, Ben G. H.
Pollard, Katherine S.
Kidder, Wesley
Melamed, Jonathan
Sandy, Moriah
Lam, Kathy N.
Lee, Joyce V.
Atreya, Chloe E.
Malig, Ysabella Noelle Amora
Venook, Alan
Turnbaugh, Peter J.
Van Blarigan, Erin L.
Gerona, Roy R.
Gempis, Daryll
Kyaw, Than S.
Goga, Andrei
Spanogiannopoulos, Peter
Bradley, Patrick H.
AuthorAffiliation 8 Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA, 94158, USA
3 Department of Microbiology, The Ohio State University, Columbus, OH 43210, USA
7 UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA
11 Bakar Computational Health Sciences Institute, University of California, San Francisco, CA 94143, USA
5 Clinical Toxicology and Environmental Biomonitoring Laboratory, University of California, San Francisco, CA, 94115, USA
2 Gladstone Institutes, San Francisco, CA 94158, USA
6 Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
1 Department of Microbiology & Immunology, University of California San Francisco, San Francisco, CA 94143, USA
4 Department of Cell & Tissue Biology, University of California San Francisco, San Francisco, CA 94143, USA
9 Department of Urology, University of California, San Francisco, San Francisco, CA 94158, USA
10 Institute for Human Genetics, Uni
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/36138165$$D View this record in MEDLINE/PubMed
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Equal contributions
Author Contributions Statement
P.J.T conceived of the project and was the primary supervisor for the study. R.R.G., A.G., and K.S.P. also supervised components of this work. P.S. led the in vitro screens and E. coli strain construction and established protocols for the pharmacokinetics and xenograft experiments. T.S.K. led the final pharmacokinetics, xenograft, transcriptomics, and amplicon sequencing data generation and analysis. B.G.H.G. led the biochemical characterization of PreTA. P.H.B. led the bioinformatic analysis of preTA operons across genomes and microbiomes. J.M., Y.N.A.M., T.S.K., B.G.H.G., and M.S. performed mass spectrometry. K.N.L. sequenced and analyzed the drug resistant E. coli mutants. J.V.L. assisted with the tumor xenograft measurements. C.E.A., A.V., and W.K. (GO Study PI) oversaw the conception and design of the GO Study and contributed patient samples. E.L.V.B. contributed to developing the study protocol and supervision of data collection for the GO Study. D.G. designed the GO Study Specimen Collection Kits and managed biospecimen collection, storage, and retrieval. P.S. wrote the initial draft. T.S.K. and P.J.T. revised the manuscript with input from all authors.
ORCID 0000-0001-9127-0986
0000-0002-0888-2875
0000-0001-9694-7263
0000-0002-7933-8615
0000-0002-9870-6196
0000-0002-5981-7766
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PMID 36138165
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Snippet Pharmaceuticals have extensive reciprocal interactions with the microbiome, but whether bacterial drug sensitivity and metabolism is driven by pathways...
Pharmaceuticals have extensive reciprocal interactions with the microbiome, but whether bacterial drug sensitivity and metabolism are driven by pathways...
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Animals
Antibacterial activity
Antineoplastic Agents - metabolism
Antineoplastic Agents - pharmacology
Antitumor agents
Bacteria - genetics
Bioavailability
Biomedical and Life Sciences
Cancer
Colorectal carcinoma
Drug metabolism
Escherichia coli
Escherichia coli - genetics
Escherichia coli - metabolism
Fluorouracil - metabolism
Fluorouracil - pharmacology
Humans
Infectious Diseases
Intestinal microflora
Life Sciences
Mammalian cells
Mammals
Medical Microbiology
Metabolic Networks and Pathways
Metabolic pathways
Metabolism
Metabolites
Mice
Microbiology
Microbiomes
Parasitology
Virology
Title Host and gut bacteria share metabolic pathways for anti-cancer drug metabolism
URI https://link.springer.com/article/10.1038/s41564-022-01226-5
https://www.ncbi.nlm.nih.gov/pubmed/36138165
https://www.proquest.com/docview/2718766914
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https://pubmed.ncbi.nlm.nih.gov/PMC9530025
Volume 7
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