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

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.

SUBMITTER: Shen S

PROVIDER: S-EPMC5575957 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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

Shen Shiqian S Lim Grewo G You Zerong Z Ding Weihua W Huang Peigen P Ran Chongzhao C Doheny Jason J Caravan Peter P Tate Samuel S Hu Kun K Kim Hyangin H McCabe Michael M Huang Bo B Xie Zhongcong Z Kwon Douglas D Chen Lucy L Mao Jianren J

Nature neuroscience 20170717 9

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 macro ...[more]

PMID: 28714953

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Project description:There has been a rapid increase in neonates born with a history of prenatal opioid exposure. How prenatal opioid exposure affects pain sensitivity in offspring is of interest, as this may perpetuate the opioid epidemic. While few studies have reported hypersensitivity to thermal pain, potential mechanisms have not been described. This study posits that alterations in the gut microbiome may underly hypersensitivity to pain in prenatally methadone-exposed 3-week-old male offspring, which were generated using a mouse model of prenatal methadone exposure. Fecal samples collected from dams and their offspring were subjected to 16s rRNA sequencing. Thermal and mechanical pain were assessed using the tail flick and Von Frey assays. Transcriptomic changes in whole brain samples of opioid or saline-exposed offspring were investigated using RNA-sequencing, and midbrain sections from these animals were subjected to qPCR profiling of genes related to neuropathic and inflammatory pain pathways. Prenatal methadone exposure increased sensitivity to thermal and mechanical pain and elevated serum levels of IL-17a. Taxonomical analysis revealed that prenatal methadone exposure resulted in significant alterations in fecal gut microbiota composition, including depletion of Lactobacillus, Bifidobacterium, and Lachnospiracea sp and increased relative abundance of Akkermansia, Clostridium sensu stricto 1, and Lachnoclostridium. Supplementation of the probiotic VSL#3 in dams rescued hypersensitivity to thermal and mechanical pain in prenatally methadone-exposed offspring. Similarly, cross-fostering prenatally methadone-exposed offspring to control dams also attenuated hypersensitivity to thermal pain in opioid-exposed offspring. Modulation of the maternal and neonatal gut microbiome with probiotics resulted in transcriptional changes in genes related to neuropathic and immune-related signaling in whole brain and midbrain samples of prenatally methadone-exposed offspring. Together, our work provides compelling evidence of the gut-brain-axis in mediating pain sensitivity in prenatally opioid-exposed offspring.

Project description:Emerging evidence suggests that gut microbiota may influence the response to chemotherapy. We sought to characterize the effects of 5 fluorouracil (5FU) chemotherapy on colon inflammation and functional measures in colorectal cancer (CRC) and to further determine whether gut microbiota can influence this response. 50 C57BL/6 were randomized into four groups; Control?+?Vehicle (n?=?10), Control?+?5FU (n?=?10), AOM/DSS?+?Vehicle (n?=?15), and AOM/DSS?+?5FU (n?=?15). CRC was induced chemically by a single 10?mg/kg injection of azoxymethane (AOM) followed by two cycles (2% and 1%) of dextran sodium sulfate (DSS). Mice were then treated with 3 cycles of vehicle or 5FU (cycle 1: 40?mg/kg, cycle 2?+?3: 20?mg/kg). Functional tests (grip strength and run-to-fatigue) were performed prior to 5FU treatment (baseline) and at the completion of the second cycle of 5FU. Following the third 5FU cycle, mice were euthanized and the colon was evaluated for expression of inflammatory genes using RT-qPCR and stool samples were profiled using 16S rRNA sequencing. A second experiment used fecal microbiota transplantation from 5FU treated mice to control mice (n?=?10-15/group) to determine whether 5FU associated changes in the microbiota could influence functional measures and colon inflammation. 5FU reduced grip strength (p?<?0.05) and caused a trending decrease in run-to-fatigue performance in cancer mice (p?=?0.06). Select intestinal inflammatory genes were significantly elevated with 5FU treatment and this was further exacerbated with cancer (p?<?0.05). Microbiota analysis revealed increased dissimilarity and alterations in bacterial taxonomy in 5FU and AOM/DSS-treated mice (p?<?0.05). Fecal transplant from 5FU treated mice reduced functional performance (p?<?0.05) and altered select colon inflammatory markers (p?<?0.05). This study provides evidence of an effect of 5FU on inflammatory responses and functional measures in a mouse model of CRC and suggests that gut microbes may play a role in some, but not all, 5FU related perturbations.

Dataset Information

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

Publications

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

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