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

摘要 有很大比例的乳腺癌幸存者--其中24%到68%--报告了共同发生的精神神经病 (PN)症状或PN症状群(定义为疼痛、疲劳和睡眠障碍的群) 在癌症治疗之后。针灸是一种安全和全面的治疗方法，可缓解癌症相关疾病 症状，包括PN症状。然而，其在治疗多发性PN症状中的作用和机制 同时，目前仍不清楚。代谢组学可以揭示系统的代谢变化和时间效应 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。目前尚不清楚针刺对PN症状的影响是否与调节有关 炎症诱导的Trp-Kyn通路的激活或与其他新通路相关。这 R21的S对这些突出问题的创新方法包括对乳房进行综合分析 针灸干预前后癌症存活者的血清和粪便代谢组及微生物组。 目的：了解针刺治疗慢性盆腔炎症候群的疗效及机制。 乳腺癌幸存者。具体目的是：(1)评估一项为期5周的针灸干预是否 降低PN症状群(疼痛、疲劳和睡眠障碍的综合评分)的严重程度， 以及乳腺癌幸存者的3种单独的PN症状；(2)确定 假设针灸后PN症状群和每个PN症状的严重程度降低 与靶向Trp-Kyn途径代谢产物的变化有关；以及(3)探索 血清、粪便代谢组和肠道微生物组中非靶向生物标志物的变化 PN症状簇和每个PN症状。我们假设针灸会减轻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 在代谢组和微生物组中。这种大规模代谢组学和微生物组标记与 PN症状表型将促进对针灸机理的理解，并识别新的 可用于未来个性化针灸治疗症状方法研究的生物标志物 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.