Unraveling the link of sleep to IBS: A Metabolomics Approach

肠易激综合征（IBS）影响全世界10-20%的成年人（女性>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）和病理生理学方面是一种异质性疾病。IBS患者报告了许多共病状况和症状，包括睡眠不良。在日常的基础上，前一天晚上睡眠不好是IBS患者第二天胃肠道（GI）症状以及心理困扰的预测因素。此外，有证据表明，皮质醇水平在夜间较高，至少在IBS患者的一个亚组中。然而，睡眠和内脏敏感性以及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，可以区分患有IBS伴睡眠不良的患者亚组。这些发现可能导致从肠道模式加上腹痛/不适症状到包括睡眠不良和生物标志物等共病状况的范式转变。该研究将利用来自59名女性（年龄18-45岁;卵泡期）的样本，这些女性先前在睡眠实验室中进行了研究，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。将在西北代谢组学研究中心对从入睡前开始并在夜间持续的9份样本进行色氨酸途径代谢物的分析。以前的研究已经证明，这些代谢物（褪黑激素，5-羟色胺，kyneurinine）中的几种与睡眠，情绪状态，运动，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。方法：1）检测TRY代谢物与皮质醇/ACTH比值的关系; 2）检测TRY代谢物与皮质醇/ACTH比值的关系; 3）检测睡眠质量（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与其他代谢途径和靶向的皮质醇相关基因关联的关系。基于初步的工作，我们假设，褪黑激素/烟酰胺的比例将在IBS妇女相比，控制较低;皮质醇将与褪黑激素呈负相关;睡眠质量的自我报告（日记，PSQI）和睡眠效率也将与褪黑激素呈正相关。代谢指纹图谱（150种代谢物）与限速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不良与常见疾病的关系，并设计最佳的治疗方法。

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.