The role of brain-gut microbiome interactions in mediating IBS and constipation symptoms during menses and menopause

脑肠微生物组相互作用在介导月经和更年期IBS和便秘症状中的作用

• 批准号: 10461217
• 负责人: Lin Chang
• 金额: $ 49.58万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10461217
• 关键词: Abdominal Pain; Affect; Arousal; Bile Acids; Brain; Brain Stem; Butyrates; Cell Nucleus; Chronic; Colon; Communication; Constipation; Data; Defecation; Development; Disease; Emotional; Emotions; Estrogens; Female; Functional disorder; Funding; Genes; Grant; Health Care Visit; Investigation; Irritable Bowel Syndrome; Lead; Link; Luteal Phase; Measures; Mediating; Menopause; Menstrual cycle; Menstruation; Metagenomics; Microbe; Modeling; Pain; Perception; Phase; Plasma; Play; Pontine structure; Postmenopause; Premenopause; Prevalence; Progesterone; Public Health; Quality of life; Research Project Grants; Rest; Ribosomal RNA; Role; Severities; Sex Differences; Shotguns; Signal Transduction; Symptoms; System; Testing; Time; Tryptophan; Visceral; Woman; base; brain magnetic resonance imaging; cost; effective therapy; endophenotype; executive function; experience; gastrointestinal symptom; gut microbiome; gut-brain axis; insight; male; men; metabolomics; microbial; microbiome; multimodality; neuroimaging; novel; patient subsets; proliferative phase Menstrual cycle; response; sensory input

ABSTRACT Irritable bowel syndrome (IBS) and chronic (functional) constipation have a worldwide prevalence of 11.2% and 14%, respectively and are more common in women than men. However, the pathophysiology of IBS and normal transit constipation (the largest subtype of chronic constipation) is incompletely understood and this likely contributes to the fact that treatments are only efficacious in a subset of patients. Significant sex-related differences include increased severity of gastrointestinal (GI) symptoms in women compared to men and during menopause and in the premenses and menses phase of the menstrual cycle which are states of depleted or declining estrogen. Based on previous studies and our preliminary data, our general hypotheses are: 1) IBS symptom severity in female IBS increases during times of low or declining estrogen states, namely in menopause and mid to late-luteal phase of the menstrual cycle, and is due to reduced estrogen-dependent corticolimbic inhibition of emotional arousal networks, resulting in enhanced visceral perception. Alterations in circulating gut microbial metabolites, in particular tryptophan, estrogen, and bile acids affecting brain stem nuclei may play an additional role, and 2) The increased prevalence and severity of normal transit constipation in women (in the absence of changes in transit or defecation), is due to altered perception of normal, non- noxious afferent signals from the colon resulting from altered central processing. This is due to widespread changes in sensorimotor, salience, and emotional arousal networks and is in part related to increased input from ascending arousal systems originating in brainstem nuclei. Changes in the activity of and ascending projections from these brainstem nuclei may be related in part to the influence of gut microbial metabolites and of estrogen. We will test these hypotheses in two specific aims in which we will measure the relative abundance of gut microbial taxa (16S rRNA), total microbial gene content (shotgun metagenomics), plasma and fecal metabolites (commercial metabolomic platform), and multimodal brain MRI (functional resting state connectivity and pain threat evoked responses) in female subjects: 1) Compare GI symptoms and BGM interactions in premenopausal and postmenopausal female IBS and healthy controls (HCs) and 2) Compare BGM interactions in premenopausal females with normal transit constipation with slow transit constipation and HCs. We anticipate that our findings will identify novel endophenotypes that can lead to the development of novel treatment approaches.

抽象的 肠易激综合症 (IBS) 和慢性（功能性）便秘的全球患病率为 11.2% 分别为 14%，女性比男性更常见。然而，IBS 的病理生理学和 正常转运便秘（慢性便秘的最大亚型）尚不完全清楚，这 这可能导致治疗仅对一小部分患者有效。与性别显着相关 差异包括与男性相比，女性胃肠道 (GI) 症状更严重 在更年期以及月经周期的经前期和经期阶段，这些状态 雌激素耗尽或下降。根据之前的研究和我们的初步数据，我们的一般假设 是： 1) 在雌激素水平较低或下降期间，女性 IBS 的 IBS 症状严重程度会增加，即 在更年期和月经周期的黄体中后期，这是由于雌激素依赖性减少所致 皮质边缘抑制情绪唤醒网络，从而增强内脏知觉。改动于 循环肠道微生物代谢物，特别是影响脑干的色氨酸、雌激素和胆汁酸 细胞核可能发挥额外的作用，2) 正常转运便秘的患病率和严重程度增加 对于女性（在转运或排便没有变化的情况下），是由于对正常的、非 由于中央处理改变而产生的来自结肠的有害传入信号。这是由于广泛 感觉运动、显着性和情绪唤醒网络的变化，部分与输入的增加有关 来自起源于脑干核团的上行唤醒系统。活动的变化和上升 这些脑干核的投射可能部分与肠道微生物代谢物的影响有关 雌激素。我们将在两个具体目标中测试这些假设，在这两个目标中我们将衡量相对 肠道微生物类群丰度 (16S rRNA)、总微生物基因含量（鸟枪法宏基因组学）、血浆 和粪便代谢物（商业代谢组学平台），以及多模式脑 MRI（功能性静息状态） 女性受试者中的连通性和疼痛威胁诱发反应：1）比较胃肠道症状和背景音乐 绝经前和绝经后女性 IBS 与健康对照 (HC) 的相互作用以及 2) 比较 BGM 在正常传输型便秘、慢传输型便秘和绝经前女性中的相互作用 HC。我们预计我们的研究结果将确定新的内表型，从而导致发展 新的治疗方法。