Editorial pubs.acs.org/chemneuro
Emerging Data Strengthens the Argument That the Microbiome Is the Fifth Horseman of the Drug Discovery Apocalypse n a recent editorial,1 I discussed a report in Science that described the influence of individual vaginal microbiomes on drug efficacy and HIV acquisition,2 and the implications of these findings on the gut−brain axis (GBA),3 as well as graver concerns for drug discovery in general. Advances in DMPK and toxicology science have largely ablated the first three Horsemen of the drug discovery apocalypse (bioavailability in man, metabolism in man, and toxicology in man), but the fourth, efficacy in man, still persists as a major reason for drug failure.4 How prominent is the influence of individual gut bacteria microbiomes on drug efficacy? As stated in the previous editorial, “Is the Microbiome the Fifth Horseman of the Apocalypse in Drug Discovery?”1 If so, the complexity of global drug development becomes enormous. Clearly, the biomedical research community is in tune with this concern, and studies are emerging that give more credence to the Fifth Horseman scenario. A recent review details gut microbiota can modulate host response to chemotherapeutic drugs in terms of drug efficacy, abrogation of anticancer effects, and the mediation of toxicity.5 In the oncology setting, both human and animal data now support a defined role, and intimate linkage, of gut bacteria and the pharmacological effects of diverse chemotherapeutic agents such as 5-fluorouracil, oxaliplatin, cyclophosphamide, gemcitabine, as well as the “hot” immunotherapies anti-PD-L1 and anti-CLTA-4 antibodies.5 Gut bacteria modulate these agents through the “TIMER” mechanistic framework: Translocation, Immunomodulation, Metabolism, Enzymatic degradation, and Reduced diversity and ecological variation.5 Thus, in oncology, strategies are in place to leverage and target microbiota to improve chemotherapeutic efficacy while simultaneously reducing toxicity. Are there examples relevant to neuroscience? Yes. A recent Nature Neuroscience report discusses how gut microbiota is critical for the induction of chemotherapy-induced pain.6 As reported by Shen and co-workers,6 gut microbiota promotes the development of chemotherapy-induced mechanical hyperalgesia, a dose-limiting condition in ∼30% of cancer patients. In their study, oxaliplatin-induced mechanical hyperalgesia was diminished in both germ-free mice and those pretreated with antibiotics. Importantly, restoration of the microbiota in the germ-free mice abrogated this protection from pain induced by oxaliplatin.6 This is a key finding, in that microbiota also regulate the drug efficacy, abrogation of anticancer effects, and the mediation of toxicity of oxaliplatin.5 Considering the role of the GBA in neuroscience, specifically, the role of microbiota on the maturation of microglia in the CNS and on neutrophil migration in inflammatory responses, the implications are broad.6 In the previous editorial on this topic, I posed the question “Could the microbiome be the Fifth Horseman of the Apocalypse in drug discovery, or is its role of little concern?” Data is emerging that does strongly suggest that the microbiome is the Fifth Horseman of the Apocalypse in drug discovery, and the implications of this will require significant
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effort across disciplines to rectify and move forward into translation. The oncology field has embraced the Fifth Horseman and is making great strides, and new data shows how the Fifth Horseman can modulate pain. What will be next? This is an exciting time in research. At ACS Chemical Neuroscience, I welcome Letters, Articles, Reviews, Perspectives, and Viewpoints on these topics, and I am eager to see more linkages of microbiota and the GBA to the efficacy/metabolism of CNS agents.
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Craig W. Lindsley, Editor-in-Chief AUTHOR INFORMATION
ORCID
Craig W. Lindsley: 0000-0003-0168-1445 Notes
Views expressed in this editorial are those of the author and not necessarily the views of the ACS.
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REFERENCES
(1) Conrad, J. A., and Lindsley, C. W. (2017) Is the Microbiome the Fifth Horseman of the Apocalypse in Drug Discovery? Implications for the Gut−Brain Axis. ACS Chem. Neurosci. 8, 1430. (2) Klatt, N. R., Cheu, R., Birse, K., Zevin, A. S., Perner, M., NoelRomas, L., Grobler, A., Westmacott, G., Xie, I. Y., Butler, J., Mansoor, L., McKinnon, L. R., Passmore, J. S., Karim, Q. A., Karim, S. S. A., and Burgener, A. D. (2017) Vaginal bacteria modify HIV tenofovir microbiocide efficacy in African women. Science 356, 938− 945. (3) Tse, J. K. Y. (2017) Gut microbiota, nitric oxide and microglia as prerequisites for neurodegenerative disorders. ACS Chem. ACS Chem. Neurosci. 8, 1438−1447. (4) Arrowsmith, A., and Miller, P. (2013) Trial Watch: Phase II and Phase III attrition rates 2011−2012. Nat. Rev. Drug Discovery 12, 569. (5) Alexander, J. L., Wilson, I. D., Teare, J., Marchesi, J. R., Nicholson, J. K., and Kinross, J. M. (2017) Gut microbiota modulation of efficacy and toxicity. Nat. Rev. Gastroenterol. Hepatol. 14, 356−365. (6) Shen, S., Lim, G., You, Z., Ding, W., Huang, P., Ran, C., Doheny, J., Caravan, P., Tate, S., Hu, K., Kim, H., McCabe, M., Huang, B., Xie, Z., Kwon, D., Chen, L., and Mao, J. (2017) Gut microbiota is critical for the induction of chemotherapy-induced pain. Nat. Neurosci., DOI: 10.1038/nn.4606.
Published: September 20, 2017 1813
DOI: 10.1021/acschemneuro.7b00295 ACS Chem. Neurosci. 2017, 8, 1813−1813
