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

摘要 肠易激综合征(IBS)和慢性(功能性)便秘在全球的患病率为11.2%， 分别为14%，女性比男性更常见。然而，IBS和IBS的病理生理学 正常传输型便秘(慢性便秘的最大亚型)还不完全了解，这 可能导致治疗只对一部分患者有效的事实。与性有关的重大问题 不同之处包括女性胃肠道(GI)症状比男性更严重， 在绝经期间以及在月经周期的前期和经期，这是一种 雌激素耗尽或下降。基于之前的研究和我们的初步数据，我们的一般假设 1)女性IBS的症状严重程度在雌激素水平低或下降的时候增加，即 在更年期和月经周期的黄体期中后期，这是由于对雌激素的依赖减少 皮质边缘抑制情绪唤醒网络，导致增强内脏知觉。中的更改 循环肠道微生物代谢产物，特别是影响脑干的色氨酸、雌激素和胆汁酸 核团可能发挥额外的作用，以及2)正常传输性便秘的患病率和严重性的增加 在女性中(在运输或排便没有变化的情况下)，是由于改变了对正常、非 来自结肠的有害传入信号是由改变的中央处理引起的。这是由于普遍存在的 感觉运动、突显和情绪唤醒网络的变化，部分与增加输入有关 来自起源于脑干核团的提升觉醒系统。活动和上升中的变化 这些脑干核团的投射可能部分与肠道微生物代谢产物和 雌激素。我们将在两个特定的目标中测试这些假设，我们将在其中测量相对 肠道微生物区系丰度(16S RRNA)、微生物总基因含量(鸟枪式元基因组学)、血浆 和粪便代谢物(商业代谢物平台)和多模式脑MRI(功能静息状态 女性受试者的连通性和疼痛威胁诱发反应：1)比较胃肠道症状和BGM 绝经前后女性肠易激综合征与健康对照的相互作用及2)比较 绝经前女性正常传输型便秘伴慢传输型便秘与BGM的相互作用 HCS。我们预计，我们的发现将确定新的内表型，可以导致发展 新的治疗方法。

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.