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Gut microbiota modulation of chemotherapy efficacy and toxicity

Key Points

  • Evidence is increasing that the gut microbiota modulate the actions of chemotherapeutic drugs used in cancer and other diseases

  • We propose the 'TIMER' mechanistic framework to explain how gut bacteria influence chemotherapy effects on the host: Translocation, Immunomodulation, Metabolism, Enzymatic degradation and Reduced diversity and ecological variation

  • A number of tools for manipulating the gut microbiota in this context, including dietary modifications, probiotics and synthetically engineered bacteria, are in development

  • The gut microbiota will be central to the future of personalized cancer treatment strategies

Abstract

Evidence is growing that the gut microbiota modulates the host response to chemotherapeutic drugs, with three main clinical outcomes: facilitation of drug efficacy; abrogation and compromise of anticancer effects; and mediation of toxicity. The implication is that gut microbiota are critical to the development of personalized cancer treatment strategies and, therefore, a greater insight into prokaryotic co-metabolism of chemotherapeutic drugs is now required. This thinking is based on evidence from human, animal and in vitro studies that gut bacteria are intimately linked to the pharmacological effects of chemotherapies (5-fluorouracil, cyclophosphamide, irinotecan, oxaliplatin, gemcitabine, methotrexate) and novel targeted immunotherapies such as anti-PD-L1 and anti-CLTA-4 therapies. The gut microbiota modulate these agents through key mechanisms, structured as the 'TIMER' mechanistic framework: Translocation, Immunomodulation, Metabolism, Enzymatic degradation, and Reduced diversity and ecological variation. The gut microbiota can now, therefore, be targeted to improve efficacy and reduce the toxicity of current chemotherapy agents. In this Review, we outline the implications of pharmacomicrobiomics in cancer therapeutics and define how the microbiota might be modified in clinical practice to improve efficacy and reduce the toxic burden of these compounds.

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Figure 1: An overview of the TIMER microbiota–host interactions that modulate chemotherapy efficacy and toxicity.
Figure 2: A model for the future analysis and translation of the oncomicrobiome for improved cancer outcomes.

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J.L.A., I.D.W. and J.M.K. researched data for the article. All authors contributed equally to discussion of content, writing and reviewing/editing the manuscript before submission.

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Correspondence to Julian R. Marchesi.

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J.K.N. is a nonexecutive director for Metabometrix and consultant for Waters Corporation and Nestle Research Centre. The other authors declare no competing interests.

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Alexander, J., Wilson, I., Teare, J. et al. Gut microbiota modulation of chemotherapy efficacy and toxicity. Nat Rev Gastroenterol Hepatol 14, 356–365 (2017). https://doi.org/10.1038/nrgastro.2017.20

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