Unraveling the link of sleep to IBS: A Metabolomics Approach

描述(由申请人提供)：肠易激综合征(IBS)在世界范围内影响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，IBS在临床表现(腹泻与便秘)和病理生理学方面都是一种不同的情况。IBS患者报告了许多共病情况和症状，包括睡眠不佳。在日常生活中，前一天晚上睡眠不佳是IBS患者胃肠道(GI)症状和第二天心理困扰的预测指标。此外，有证据表明，至少在一部分IBS患者中，夜间皮质醇水平较高。然而，睡眠、内脏敏感性和肠道症状之间的联系仍然有限。这项拟议的研究的重点是描述一种代谢途径，这种代谢途径可以区分出一部分患有IBS并伴有睡眠不良的患者。这些发现可能会导致范式的转变，从肠道模式加上腹痛/不适症状，转变为包括睡眠不良和生物标志物等共病情况的模式。这项研究将利用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了研究，并获得了系列血液样本、多导睡眠图、促肾上腺皮质激素、皮质醇和靶向遗传标记。西北新陈代谢研究中心将对9个样本在入睡前和夜间继续进行检测，以检测色氨酸途径中的代谢物。先前的研究已经证明，这些代谢物中的几种(褪黑激素、5-羟色胺、基神经氨酸)与睡眠、情绪状态、运动、疼痛敏感性和炎症有关。因此，这项研究的目的是比较睡眠前和睡眠期间9次收集的血浆代谢物，以1)描述和比较女性(18-45岁)的血浆色氨酸(Try)代谢物模式。2)测试Try代谢物与皮质醇/ACTH比值的关系；3)测试睡眠质量(PSQI、PSG、睡眠日记)与Try代谢物类型的关系；以及4)探索睡眠质量指标、皮质醇和ACTH与其他代谢途径和靶向5-羟色胺相关基因关联的关系。在前期工作的基础上，我们假设IBS女性的褪黑激素/烟酰胺比率将低于对照组；皮质醇与褪黑激素呈负相关；对睡眠质量(日记，PSQI)和睡眠效率的自我报告也将与褪黑激素呈正相关。代谢指纹图谱(150种代谢物)结合限速色氨酸羟基酶基因的遗传多态性，将使我们能够进一步阐明睡眠不良与常见疾病的关系，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.