Unraveling the link of sleep to IBS: A Metabolomics Approach

阐明睡眠与 IBS 的联系：代谢组学方法

• 批准号: 8764334
• 负责人: Margaret McLean Heitkemper
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8764334
• 关键词: Abdomen; Abdominal Pain; Accounting; Adult; Affect; Age; Attention; Betaine; Biological; Biological Assay; Biological Markers; Blood specimen; Cell physiology; Clinical; Constipation; Corticotropin; Data; Development; Diarrhea; Distress; Economics; Emotional; Enterochromaffin Cells; Essential Amino Acids; Etiology; Exhibits; Fatigue; Feasibility Studies; Fingerprint; Frequencies; Functional disorder; Gastrointestinal tract structure; Genes; Genetic Markers; Genetic Polymorphism; Goals; Headache; Health; Homocysteine; Homocystine; Hydrocortisone; Inflammation; Intestines; Irritable Bowel Syndrome; Laboratories; Link; Measures; Melatonin; Mental Depression; Metabolic Pathway; Methionine; Moods; Musculoskeletal Pain; Neuraxis; Niacinamide; Pain; Pathway interactions; Patient Self-Report; Patients; Pattern; Pelvic Pain; Permeability; Persons; Physiological; Plasma; Polysomnography; Production; Quality Indicator; Reporting; Research; Sampling; Schools; Science; Serotonin; Serum; Severities; Site; Sleep; Sleeplessness; Subgroup; Symptoms; Testing; Therapeutic; Time; Tryptophan; Tryptophan 5-monooxygenase; Tryptophan Metabolism Pathway; Validation; Visceral; Woman; Work; abstracting; base; cell motility; design; diaries; gastrointestinal; gastrointestinal symptom; liquid chromatography mass spectrometry; men; metabolomics; neurochemistry; novel therapeutic intervention; patient population; proliferative phase Menstrual cycle; psychological distress; public health relevance; sleep onset; social; Abdomen; Abdominal Pain; Accounting; Adult; Affect; Age; Attention; Betaine; Biological; Biological Assay; Biological Markers; Blood specimen; Cell physiology; Clinical; Constipation; Corticotropin; Data; Development; Diarrhea; Distress; Economics; Emotional; Enterochromaffin Cells; Essential Amino Acids; Etiology; Exhibits; Fatigue; Feasibility Studies; Fingerprint; Frequencies; Functional disorder; Gastrointestinal tract structure; Genes; Genetic Markers; Genetic Polymorphism; Goals; Headache; Health; Homocysteine; Homocystine; Hydrocortisone; Inflammation; Intestines; Irritable Bowel Syndrome; Laboratories; Link; Measures; Melatonin; Mental Depression; Metabolic Pathway; Methionine; Moods; Musculoskeletal Pain; Neuraxis; Niacinamide; Pain; Pathway interactions; Patient Self-Report; Patients; Pattern; Pelvic Pain; Permeability; Persons; Physiological; Plasma; Polysomnography; Production; Quality Indicator; Reporting; Research; Sampling; Schools; Science; Serotonin; Serum; Severities; Site; Sleep; Sleeplessness; Subgroup; Symptoms; Testing; Therapeutic; Time; Tryptophan; Tryptophan 5-monooxygenase; Tryptophan Metabolism Pathway; Validation; Visceral; Woman; Work; abstracting; base; cell motility; design; diaries; gastrointestinal; gastrointestinal symptom; liquid chromatography mass spectrometry; men; metabolomics; neurochemistry; novel therapeutic intervention; patient population; proliferative phase Menstrual cycle; psychological distress; public health relevance; sleep onset; social

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.

描述（由申请人提供）：抽象的肠易激综合症（IBS）影响全球10-20％的成年人（女性>男性），造成了巨大的经济，社会和情感负担。越来越清楚的是，就临床表现（腹泻与便秘）和病理生理学而言，IBS是一种异质疾病。 IBS患者报告了许多合并症状况和症状，包括睡眠不佳。前一天晚上睡眠不佳的日常睡眠是胃肠道（GI）症状以及第二天在IBS患者中的心理困扰的预测指标。此外，有证据表明，至少在IBS患者亚组中，夜间皮质醇水平较高。然而，连接睡眠和内脏敏感性和肠症状如何保持限制。拟议的研究的重点是表征一种代谢途径，该途径可能会区分睡眠不良的IBS患者亚组。发现可能导致从肠模式加上腹痛/不适症状转变为涵盖诸如睡眠不良和生物标记等合并状况的症状。该研究将利用先前在睡眠实验室中研究的59名女性（年龄18-45岁的卵泡期）的样本，其中串行血液样本，多肌液术，肾上腺皮质性激素，皮质醇和靶向遗传标记。在色氨酸途径中的西北代谢组学研究中心，将在睡眠开始前和夜间继续进行九个样本。先前的研究表明，这些代谢产物中的几种（褪黑激素，5-羟色胺，kyneurinine）与睡眠，情绪状态，运动，疼痛敏感性和炎症有关。因此，该研究的目的是将睡眠前后9次聚集的血浆代谢产物与1）描述和比较女性（年龄18-45岁）与IBS（n = 38）中的血浆（TRY）代谢物模式与HC（n = 21）； 2）测试尝试代谢产物与皮质醇/ACTH比率的关系； 3）测试睡眠质量（PSQI，PSG，睡眠日记）与尝试代谢物模式的关系； 4）探索睡眠质量指标，皮质醇和ACTH与其他代谢途径以及靶向5-羟色胺相关基因相关的关系。基于初步工作，我们假设IBS女性与对照组相比，IBS妇女的褪黑激素/烟酸胺比率将较低。皮质醇将与褪黑激素负相关；睡眠质量的自我报告（日记，PSQI）和睡眠效率也将与褪黑激素正相关。代谢组指纹（150个代谢产物）结合了限制速率的色氨酸羟化酶基因中的遗传多态性，这将使我们能够进一步阐明睡眠与常见状态和设计最佳治疗方法的贫穷睡眠关系。