Unraveling the link of sleep to IBS: A Metabolomics Approach

摘要肠易激综合征（IBS）影响全球10-20%的成年人（女性和男性），造成巨大的经济、社会和情感负担。越来越清楚的是，肠易激综合征在临床表现（腹泻与便秘）和病理生理方面都是一种异质性疾病。肠易激综合征患者报告了许多合并症和症状，包括睡眠不佳。在日常的基础上，前一天晚上的睡眠不足是肠易激综合征患者胃肠道（GI）症状和第二天心理困扰的一个预测指标。此外，有证据表明，至少在肠易激综合征患者的一个亚组中，皮质醇水平在夜间较高。然而，睡眠与内脏敏感性和肠道症状之间的联系仍然有限。拟议研究的重点是表征代谢途径，该途径可能区分IBS患者共病性睡眠不足亚组。研究结果可能导致范式转变，从肠道模式加腹痛/不适症状转变为包含睡眠不良和生物标志物等共病条件的模式。该研究将利用59名女性（年龄18-45岁；卵泡期）的样本，这些样本之前在睡眠实验室进行过研究，并获得了一系列血液样本、多导睡眠图、促肾上腺皮质激素、皮质醇和靶向遗传标记。在西北代谢组学研究中心，从睡眠开始到夜间持续的9个样本将被检测色氨酸途径中的代谢物。先前的研究表明，这些代谢物中的一些（褪黑激素、血清素、kyneurinine）与睡眠、情绪状态、运动性、疼痛敏感性和炎症有关。因此，该研究的目的是比较在睡眠前和睡眠中收集的9次血浆代谢物，以1)描述并比较IBS （n=38）和hc （n=21）女性（18-45岁）血浆色氨酸（TRY）代谢物模式；2)检测TRY代谢物与皮质醇/ACTH比值的关系；3)检验睡眠质量（PSQI、PSG、睡眠日记）与TRY代谢物模式的关系；4)探索睡眠质量指标、皮质醇和ACTH与额外代谢途径和靶向血清素相关基因关联的关系。根据初步的研究，我们假设IBS女性的褪黑素/烟酰胺比例比对照组低；皮质醇与褪黑激素呈负相关；睡眠质量自我报告（日记、PSQI）和睡眠效率也与褪黑激素呈正相关。代谢组学指纹图谱（150种代谢物）与限制性色氨酸羟化酶基因的遗传多态性相结合，将使我们能够进一步阐明睡眠质量差与常见疾病的关系，并设计最佳治疗方法。

DESCRIPTION (provided by applicant): Abstract Irritable bowel syndrome (IBS) affects 10-20% of adults (women>men) worldwide exerting a tremendous economic, social, and emotional burden. Increasingly it is becoming clear that IBS is a heterogeneous condition both in terms of clinical presentation (diarrhea versus constipation) and pathophysiology. Patients with IBS report a number of co-morbid conditions and symptoms including poor sleep. On a day-to-day basis poor sleep the night before is a predictor of gastrointestinal (GI) symptoms as well as psychological distress the next day in IBS patients. In addition, evidence indicates that cortisol levels are higher during the night at least in a subgroup of patients with IBS. Yet, how sleep and visceral sensitivity and bowel symptoms are linked remains limited. The focus of the proposed study is on characterizing a metabolic pathway that may distinguish a subgroup of patients with IBS with comorbid poor sleep. Findings could result in a paradigm shift from bowel pattern plus abdominal pain/discomfort symptoms to one that encompasses co-morbid conditions such as poor sleep and biological markers. The study will utilize samples from 59 women (ages 18-45; follicular phase) previously studied in a sleep laboratory and in whom serial blood samples, polysomnography, adrenocorticotropic hormone, cortisol, and targeted genetic markers were obtained. Nine samples starting prior to sleep onset and continuing during the night will be assayed at the Northwest Metabolomics Research Center for metabolites that are in the tryptophan pathway. Previous research has demonstrated that several of these metabolites (melatonin, serotonin, kyneurinine) are linked with sleep, mood state, motility, pain sensitivity, and inflammation. Thus the aims of the study are to compare plasma metabolites gathered at 9 times before and during sleep to 1) describe and compare plasma tryptophan (TRY) metabolite patterns in women (18-45 yr. of age) with IBS (n=38) to HCs (n=21); 2) test the relationship of TRY metabolites with cortisol/ACTH ratio; 3) test the relationship of sleep quality (PSQI, PSG, sleep diary) with TRY metabolite patterns; and 4) explore the relationship of sleep quality indicators, cortisol and ACTH with additional metabolic pathways and targeted serotonin-related gene associations. Based on preliminary work we hypothesize that the melatonin/niacinamide ratio will be lower in IBS women compared to controls; cortisol will be negatively correlated with melatonin; self-report of sleep quality (diary, PSQI) and sleep efficiency will also be positively correlated with melatonin. Metabolomic fingerprinting (150 metabolites) combined with genetic polymorphisms in the rate-limiting tryptophan hydroxylase gene will allow us to further elucidate the relationship of poor sleep with a common condition and design optimal therapeutic approaches.