1. Computational and Systems Biology

Evolved bacterial resistance against fluoropyrimidines can lower chemotherapy impact in the Caenorhabditis elegans host

  1. Brittany Rosener
  2. Serkan Sayin
  3. Peter O Oluoch
  4. Aurian P García González
  5. Hirotada Mori
  6. Albertha JM Walhout
  7. Amir Mitchell  Is a corresponding author
  1. University of Massachusetts Medical School, United States
  2. Nara Institute of Science and Technology, Japan
https://doi.org/10.7554/eLife.59831
Share this article
Cite this article
  1. Brittany Rosener
  2. Serkan Sayin
  3. Peter O Oluoch
  4. Aurian P García González
  5. Hirotada Mori
  6. Albertha JM Walhout
  7. Amir Mitchell
(2020)
Evolved bacterial resistance against fluoropyrimidines can lower chemotherapy impact in the Caenorhabditis elegans host
eLife 9:e59831.
https://doi.org/10.7554/eLife.59831
  2. Download BibTeX
  3. Download .RIS

Abstract

Metabolism of host-targeted drugs by the microbiome can substantially impact host treatment success. However, since many host-targeted drugs inadvertently hamper microbiome growth, repeated drug administration can lead to microbiome evolutionary adaptation. We tested if evolved bacterial resistance against host-targeted drugs alters their drug metabolism and impacts host treatment success. We used a model system of C. elegans, its bacterial diet, and two fluoropyrimidine chemotherapies. Genetic screens revealed that most of loss-of-function resistance mutations in Escherichia coli also reduced drug toxicity in the host. We found that resistance rapidly emerged in E. coli under natural selection and converged to a handful of resistance mechanisms. Surprisingly, we discovered that nutrient availability during bacterial evolution dictated the dietary effect on the host – only bacteria evolving in nutrient-poor media reduced host drug toxicity. Our work suggests that bacteria can rapidly adapt to host-targeted drugs and by doing so may also impact the host.

Data availability

Sequencing data was deposited in SRA under the BioProjects IDs PRJNA645604 and PRJNA645605

The following previously published data sets were used

Article and author information

Author details

  1. Brittany Rosener

    Program in Systems Biology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Serkan Sayin

    Program in Systems Biology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Peter O Oluoch

    Program in Systems Biology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7451-4993

  4. Aurian P García González

    Program in Systems Biology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Hirotada Mori

    Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Japan
    Competing interests
    The authors declare that no competing interests exist.

  6. Albertha JM Walhout

    Program in Systems Biology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5587-3608

  7. Amir Mitchell

    Program in Systems Biology, Program in Molecular Medicine, Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, United States
    For correspondence
    amir.mitchell@umassmed.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9376-3987

Funding

NIGMS (R35GM133775)

  • Amir Mitchell

NIGMS (DK068429)

  • Albertha JM Walhout

NIGMS (GM122393)

  • Aurian P García González

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Christian R Landry, Université Laval, Canada

Version history

  1. Received: June 9, 2020
  2. Accepted: November 25, 2020
  3. Accepted Manuscript published: November 30, 2020 (version 1)
  4. Version of Record published: December 9, 2020 (version 2)

Copyright

© 2020, Rosener et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,916
    Page views
  • 224
    Downloads
  • 12
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Brittany Rosener
  2. Serkan Sayin
  3. Peter O Oluoch
  4. Aurian P García González
  5. Hirotada Mori
  6. Albertha JM Walhout
  7. Amir Mitchell
(2020)
Evolved bacterial resistance against fluoropyrimidines can lower chemotherapy impact in the Caenorhabditis elegans host
eLife 9:e59831.
https://doi.org/10.7554/eLife.59831

Categories and tags

Research organisms

Further reading

    1. Computational and Systems Biology
    2. Evolutionary Biology

    Evolved bacterial resistance to the chemotherapy gemcitabine modulates its efficacy in co-cultured cancer cells

    Serkan Sayin, Brittany Rosener ... Amir Mitchell
    Research Advance Updated

    Drug metabolism by the microbiome can influence anticancer treatment success. We previously suggested that chemotherapies with antimicrobial activity can select for adaptations in bacterial drug metabolism that can inadvertently influence the host’s chemoresistance. We demonstrated that evolved resistance against fluoropyrimidine chemotherapy lowered its efficacy in worms feeding on drug-evolved bacteria (Rosener et al., 2020). Here, we examine a model system that captures local interactions that can occur in the tumor microenvironment. Gammaproteobacteria-colonizing pancreatic tumors can degrade the nucleoside-analog chemotherapy gemcitabine and, in doing so, can increase the tumor’s chemoresistance. Using a genetic screen in Escherichia coli, we mapped all loss-of-function mutations conferring gemcitabine resistance. Surprisingly, we infer that one third of top resistance mutations increase or decrease bacterial drug breakdown and therefore can either lower or raise the gemcitabine load in the local environment. Experiments in three E. coli strains revealed that evolved adaptation converged to inactivation of the nucleoside permease NupC, an adaptation that increased the drug burden on co-cultured cancer cells. The two studies provide complementary insights on the potential impact of microbiome adaptation to chemotherapy by showing that bacteria–drug interactions can have local and systemic influence on drug activity.

    1. Computational and Systems Biology

    Homeostasis, injury and recovery dynamics at multiple scales in a self-organizing mouse intestinal crypt

    Louis Gall, Carrie Duckworth ... Carmen Pin
    Research Article

    The maintenance of the functional integrity of the intestinal epithelium requires a tight coordination between cell production, migration and shedding along the crypt-villus axis. Dysregulation of these processes may result in loss of the intestinal barrier and disease. With the aim of generating a more complete and integrated understanding of how the epithelium maintains homeostasis and recovers after injury, we have built a multi-scale agent-based model (ABM) of the mouse intestinal epithelium. We demonstrate that stable, self-organizing behaviour in the crypt emerges from the dynamic interaction of multiple signalling pathways, such as Wnt, Notch, BMP, ZNRF3/RNF43 and YAP-Hippo pathways, which regulate proliferation and differentiation, respond to environmental mechanical cues, form feedback mechanisms and modulate the dynamics of the cell cycle protein network. The model recapitulates the crypt phenotype reported after persistent stem cell ablation and after the inhibition of the CDK1 cycle protein. Moreover, we simulated 5-fluorouracil (5-FU)-induced toxicity at multiple scales starting from DNA and RNA damage, which disrupts the cell cycle, cell signalling, proliferation, differentiation and migration and leads to loss of barrier integrity. During recovery, our in-silico crypt regenerates its structure in a self-organizing, dynamic fashion driven by dedifferentiation and enhanced by negative feedback loops. Thus, the model enables the simulation of xenobiotic-, in particular chemotherapy-, induced mechanisms of intestinal toxicity and epithelial recovery. Overall, we present a systems model able to simulate the disruption of molecular events and its impact across multiple levels of epithelial organization and demonstrate its application to epithelial research and drug development.

    1. Computational and Systems Biology

    Genetics: From mouse to human

    Arya Mani
    Insight

    A deep analysis of multiple genomic datasets reveals which genetic pathways associated with atherosclerosis and coronary artery disease are shared between mice and humans.