title: Gut microbiota modulation of chemotherapy efficacy and toxicity.
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.
authors.affiliation: Centre for Digestive and Gut Health, Department of Surgery &Cancer, 10th Floor QEQM Building, St Mary's Hospital Campus, Praed Street, Imperial College London, London, W2 1NY, UK.|Computational and Systems Medicine, Department of Surgery &Cancer, Sir Alexander Fleming Building, Imperial College London, South Kensington, London, SW7 2DD, UK.
authors.forename: James L
authors.initials: JL
authors.lastname: Alexander
authors.affiliation: Computational and Systems Medicine, Department of Surgery &Cancer, Sir Alexander Fleming Building, Imperial College London, South Kensington, London, SW7 2DD, UK.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Wilson
authors.affiliation: Centre for Digestive and Gut Health, Department of Surgery &Cancer, 10th Floor QEQM Building, St Mary's Hospital Campus, Praed Street, Imperial College London, London, W2 1NY, UK.
authors.forename: Julian
authors.initials: J
authors.lastname: Teare
authors.affiliation: Centre for Digestive and Gut Health, Department of Surgery &Cancer, 10th Floor QEQM Building, St Mary's Hospital Campus, Praed Street, Imperial College London, London, W2 1NY, UK.|School of Biosciences, The Sir Martin Evans Building, Cardiff University, Museum Avenue, Cardiff, CF10 3AX, UK.|Computational and Systems Medicine, Department of Surgery &Cancer, Sir Alexander Fleming Building, Imperial College London, South Kensington, London, SW7 2DD, UK.
authors.forename: Julian R
authors.initials: JR
authors.lastname: Marchesi
authors.affiliation: Computational and Systems Medicine, Department of Surgery &Cancer, Sir Alexander Fleming Building, Imperial College London, South Kensington, London, SW7 2DD, UK.
authors.forename: Jeremy K
authors.initials: JK
authors.lastname: Nicholson
authors.affiliation: Centre for Digestive and Gut Health, Department of Surgery &Cancer, 10th Floor QEQM Building, St Mary's Hospital Campus, Praed Street, Imperial College London, London, W2 1NY, UK.|Computational and Systems Medicine, Department of Surgery &Cancer, Sir Alexander Fleming Building, Imperial College London, South Kensington, London, SW7 2DD, UK.
authors.forename: James M
authors.initials: JM
authors.lastname: Kinross
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D001424:Bacterial Infections / Q000209:etiology; D018988:Bacterial Translocation / Q000502:physiology; D044822:Biodiversity; D015415:Biomarkers; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D004032:Diet; D004195:Disease Models, Animal; D005544:Forecasting; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D000069196:Gastrointestinal Microbiome / Q000502:physiology*; D006801:Humans; D056747:Immunomodulation / Q000502:physiology; D007167:Immunotherapy / Q000379:methods; D051379:Mice; D009369:Neoplasms / Q000628:therapy*; D056692:Prebiotics / Q000382:microbiology; D019936:Probiotics / Q000494:pharmacology; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors; D058616:Synbiotics; D058615:Synthetic Biology / Q000639:trends
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D015415:Biomarkers; D060908:CTLA-4 Antigen; C105992:PDCD1 protein, human; D056692:Prebiotics; D061026:Programmed Cell Death 1 Receptor