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.
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.