A Multi-Omics Study of the Effect and Mechanisms of Acupuncture on Psychoneurological Symptoms Among Breast Cancer Survivors

摘要 很大一部分乳腺癌幸存者-其中24%至68%-报告共同发生的心理神经系统疾病 (PN)症状或PN症状簇（定义为疼痛、疲劳和睡眠障碍的簇） 以及癌症治疗后。针灸是一种安全和全面的治疗方法，可以缓解癌症相关的 包括PN症状。然而，它在治疗多种PN症状中的作用和机制 但同时也不清楚。代谢组学可以揭示系统性代谢变化和时效性 干预措施与目标疾病之间的关系。代谢组学研究表明， 色氨酸（Trp）-犬尿氨酸（Kyn）代谢途径在癌症PN症状中起关键作用 幸存者针灸对PN症状的影响是否与调节有关， 炎症诱导的Trp-Kyn通路激活或与其他新途径相关。这 R21对这些突出问题的创新方法包括对乳腺癌进行综合分析， 癌症幸存者的血清和粪便代谢组和微生物组在针灸干预前后。 目的是了解针刺治疗PN症状群的疗效和机制， 乳腺癌幸存者具体目的是：（1）评价5周针刺干预是否 降低PN症状群的严重程度（疼痛、疲劳和睡眠障碍的综合评分）， 以及乳腺癌幸存者中3种单独PN症状中的每一种;（2）确定 假设针刺后PN症状群和每种PN症状的严重程度降低 与靶向Trp-Kyn途径代谢物的变化相关;以及（3）探索 血清和粪便代谢组和肠道微生物组中非靶向生物标志物的变化以及 PN症状聚类和每个PN症状。我们假设针灸可以减轻PN症状 通过Trp-Kyn代谢途径聚集，也将影响和产生其他有益的变化 代谢组和微生物组。这种大规模代谢组学和微生物组标志物的整合 PN症状表型将促进对针灸的机制理解，并识别新的 生物标志物可用于未来个性化针灸治疗症状的研究 乳腺癌幸存者的管理和救济。

ABSTRACT A large proportion of breast cancer survivors—24% to 68% of them—report co-occurring psychoneurological (PN) symptoms or the PN symptom cluster (defined as a cluster of pain, fatigue, and sleep disturbance) during and after cancer treatment. Acupuncture is a safe and holistic treatment known to relieve cancer-related symptoms, including PN symptoms. However, its role and mechanism in treating multiple PN symptoms simultaneously remains unclear. Metabolomics can reveal systematic metabolic changes and time-effect relationships between an intervention and the targeted disease. Metabolomic studies suggest that the tryptophan (Trp)–kynurenine (Kyn) metabolic pathway plays a critical role in PN symptoms among cancer survivors. It remains unknown whether the effect of acupuncture on PN symptoms is associated with regulation of the inflammation-induced activation of the Trp-Kyn pathway or is associated with other novel pathways. This R21’s innovative approach to these outstanding questions involves performing an integrated analysis of breast cancer survivors’ serum and fecal metabolome and microbiome before and after an acupuncture intervention. The goal is to understand the effect and mechanism of acupuncture in treating the PN symptom cluster among breast cancer survivors. The specific aims are: (1) to evaluate whether a 5-week acupuncture intervention decreases the severity of the PN symptom cluster (a composite score of pain, fatigue, and sleep disturbance), as well as each of the 3 individual PN symptoms, among breast cancer survivors; (2) to determine whether the hypothesized decrease in the severity of the PN symptom cluster and each PN symptom following acupuncture is associated with changes in targeted Trp-Kyn pathway metabolites; and (3) to explore associations between changes in untargeted biomarkers in the serum and fecal metabolome and gut microbiome and the changes in the PN symptom cluster and each PN symptom. We hypothesize that acupuncture will reduce the PN symptom cluster through the Trp-Kyn metabolomic pathway and will also influence and produce other beneficial changes in the metabolome and microbiome. This integration of large-scale metabolomics and microbiome markers with PN symptom phenotypes will advance a mechanistic understanding of acupuncture and identify novel biomarkers that could be used in future studies of personalized acupuncture approaches to symptom management and relief among breast cancer survivors.