Brief Communication | Published:

Gut microbiota is critical for the induction of chemotherapy-induced pain

Nature Neuroscience volume 20, pages 12131216 (2017) | Download Citation

Abstract

Chemotherapy-induced pain is a dose-limiting condition that affects 30% of patients undergoing chemotherapy. We found that gut microbiota promotes the development of chemotherapy-induced mechanical hyperalgesia. Oxaliplatin-induced mechanical hyperalgesia was reduced in germ-free mice and in mice pretreated with antibiotics. Restoring the microbiota of germ-free mice abrogated this protection. These effects appear to be mediated, in part, by TLR4 expressed on hematopoietic cells, including macrophages.

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Acknowledgements

We thank P. Waghorn and O. Pinkhasov for assistance with the ICP-MS study, MGH COX-7 animal facility and CNY149 animal facility for animal husbandry, L. Chen for genomic data analysis, Z. Zhang and J. Moon for bone marrow transplantation, Y. Dong and J. Lan for their assistance with Tlr4-knockout animals and Q. Chen for critical comments on the manuscript. S.S. received support from NIH grant 5T32GM007592, a Foundation of Anesthesia Research and Education grant, and departmental research funds. This work was supported by NIH grant R01DE022901 (to J.M.). W.D. was supported by Hangzhou Science and Technology Plan No. 20130633B02 and Zhejiang Medical Science and Technology Plan No. 2011KYB064. The ICP-MS equipment was purchased with support from NIH grant S10OD010650.

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Affiliations

  1. MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Shiqian Shen
    • , Grewo Lim
    • , Zerong You
    • , Jason Doheny
    • , Samuel Tate
    • , Kun Hu
    • , Hyangin Kim
    • , Michael McCabe
    • , Lucy Chen
    •  & Jianren Mao
  2. Department of Anesthesia and Pain Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

    • Weihua Ding
  3. Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Peigen Huang
  4. MGH/HST Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Chongzhao Ran
    •  & Peter Caravan
  5. Basic Sciences Institute, Chinese Academy of Medical Sciences, Beijing, China.

    • Bo Huang
  6. Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Zhongcong Xie
  7. Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA.

    • Douglas Kwon
  8. Division of Infectious Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Douglas Kwon

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Contributions

S.S. and J.M. conceived the project and wrote the manuscript. S.S., G.L., Z.Y., W.D., S.T., H.K. and M.M. conducted the experiments. C.R. conducted the bioluminescence study. P.C. carried out the mass spectrometry study. P.H. performed part of the animal study. J.D. contributed to manuscript preparation. K.H. assisted the bone marrow chimera analysis. Z.X. contributed to the Tlr4-knockout mice experiment. D.K. contributed to the analysis of gene sequencing data. B.H. and L.C. contributed intellectually to the project.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Shiqian Shen or Jianren Mao.

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https://doi.org/10.1038/nn.4606

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