| Background:Chronic postoperative pain(CPP)is highly prevalent in breast cancer survivors.Prospective studies suggest that nearly one third of the breast cancer survivors experience moderate-to-severe pain after surgery.With 5-year survival rates reaching 90%after more early breast cancer screening,the improvement of surgical methods and the enhancement of perioperative adjuvant therapy,an increasing number of people now live with pain after breast cancer treatment.About 30%of breast cancer survivors have to suffer from chronic pain for up to 10 years after surgery.To alleviate postoperative pain,an increase in opioids prescription has been observed.Although the efficacy of opioids in chronic pain is satisfactory,the long-term safety of opioids remains questionable.The increase in opioids prescription has led to increasing death related to opioids misuse and overdose.Therefore,alternative non-opioid treatments for the prevention and treatment of CPP in this population is pursued.Prediction model can calculate a patient’s probability of disease,and the clinician can provide targeted prevention and intervention for the patient.In the published prospective studies,researchers have identified age,weight,preoperative psychological symptoms,and acute postoperative pain as the risk factors of CPP in breast cancer survivors.Clinical prediction models established based on these factors are used to inform a patient’s risk of CPP.However,the utility and generalization of these models are limited by geographic,racial,and dietary factors.Incorporating non-invasive and simple assessment procedures,such as gut microbiota assessment,into the traditional model to improve its discri mination will benefit patients.Gut microbiota is the most complex and populous micro-ecological system in the body.Over time,the gut microbiota has formed a symbiotic relationship with its host and has been demonstrated to contribute to the pathophysiology of some neurological conditions,including pain.Furthermore,typical features of gut microbiota have predictive potential in some pathological conditions,and the non-invasive characteristics of gut microbiota make this potential more promising.However,no study has compared the preoperative gut microbiota of breast cancer survivors with and without CPP,and it remains unknown whether differential gut microbiota prior to surgery can improve the discri mination of clinical models.Explore the pathogenesis of chronic pain can increase the in-depth understanding of the disease and provide a new intervention for clinical prevention and treatment.Neuropathic pain is the most common and difficult type to treat.Among patients with moderate to severe chronic postoperative pain,about a half of patients report that their pain to be neuropathic.Spinal microglia are important immune cells in the central system,and play an important role in central sensitization and the development of neuropathic pain through neuron-glial interactions.Microglia are known as resident macrophages in the central nervous system,widely distributed throughout the central nervous system.They can monitor the local environment of the central nervous system and respond quickly to various stimuli that threaten physiological homeostasis,including peripheral nerve injury.In previous reports,peripheral nerve injury can result in dramatic action of spinal dorsal microglia.Morphological features of microglia activation(the pro-inflammatory type,M1 phenotype)include cell body hypertrophy,thickening and shrinkage of processes,increased number of cells,and increased staining of microglia markers.It has been reported that the increase of microglial M1 phenotype could be caused by peripheral nerve injury,accompanied by the increased expression of some gene.Peroxisome proliferator-activated receptor-γ(PPAR-γ)is a class of ligand-activated nuclear transcription factors.It binds to peroxisome proliferator response elements(PPREs)of specific target gene promoter regions,regulate its transcription and a variety of nuclear target gene expression.PPAR-γ also plays an important role in the polarization of microglia to M2 type.PPAR-γ has been reported to produce analgesic effects by recruiting M2-type macrophages in inflammatory pain.Furthermore,it has been demonstrated that the action of PPAR-γ in the spinal cord can attenuate mechanical hyperalgesia of neuropathic pain induced by spared nerve injury(SNI)by promoting the polarization of spinal microglia to an anti-inflammatory phenotype(M2 microglia).However,uncertainty remains regarding the role of the PPAR-γ-microglia pathway in the regulation of neuropathic pain by the gut microbiota.Method:We combined clinical with animal experimentation to explore the relationships between preoperative gut microbiota and CPP.First,we designed a prospective cohort nested case-control study.16s rRNA sequencing was used to analyze the difference in preoperative gut microbiota between the two groups.Logical regression was used to establish a prediction model with chronic pain at 3 month after surgery as the outcome and previously reported preoperative clinical parameters as independent variables.Then,preoperative differential gut microbiota of the two groups was added to this prediction model to see whether the discri mination of the model could be improved.The purpose of the animal experimentation was to elucidate the causal relationship between preoperative gut microbiota and CPP and to explore the underlying mechanisms involved.Due to complex pathogenesis,there is no animal model special for chronic postoperative pain in breast cancer survivors.Based on the literature and the pathogenetic anatomical basis of neuropathic pain after breast cancer surgery,we adopted the neuropathic pain model induced by spared nerve injury(SNI).SNI model was established after fecal microbiota transplantation(FMT),and mechanical withdraw threshold(MWT)were tested every a week across the whole experimentation.Expression of markers of microglia,and PPAR-y in spinal cord were assessed with respect to possible mechanisms involved.Results:In total,203 female breast cancer survivors were finally included in the final analysis who provided qualified preoperative stool samples and were successfully followed up.Of all,66 patients developed CPP which constituted the chronic pain group(CPP group).Among the remaining patients without chronic pain,66 patients were selected as the control group through propensity analysis matched(PSM)by age and body mass index(BMI).The composition of preoperative gut microbiota were significantly different between the two groups at different levels.We construct a clinical predictive model for chronic pain after breast cancer surgery using previously reported risk factors for chronic pain after breast cancer surgery,including preoperative anxiety and depression as well as postoperative acute pain.The discri mination of this model was calculated by the area under the relative operating characteristic curve(ROC).Then we added the differential microbiota at family and genus level into this model and found that the discri mination of the model was improved by 3.9%and 9.9%,respectively.In animal experimentation,"CPP microbiota" recipient mice resulted in significantly decreased withdraw threshold 14 days after SNI,together with the decreased expression of PPAR-y and Arginase-1(Arg-1)in the spinal cord,indicating the causal effect of preoperative gut microbiota in CPP,probably through regulating spinal PPAR-y-microgllia pathway.Conclusions:Preoperative gut microbiota plays a causal role in the development of CPP,probably by regulating the spinal PPAR-y-microglia pathway.Preoperative gut microbiota can be used as a target for the clinical prediction and treatment of CPP in breast cancer survivors. |
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