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）便秘的全球患病率为11.2%， 14%，女性比男性更常见。然而，IBS的病理生理学和 正常传输型便秘（慢性便秘的最大亚型）尚未完全了解， 这可能导致治疗仅在一部分患者中有效。学显著性性别相关 差异包括与男性相比，女性胃肠道（GI）症状的严重程度增加， 在绝经期间以及在月经周期的经前期和月经期， 雌激素耗尽或下降。根据以往的研究和我们的初步数据，我们的一般假设， 女性IBS的症状严重程度在雌激素水平低或下降期间增加，即 在绝经期和月经周期的中期至晚期黄体期，是由于雌激素依赖性降低 皮质边缘抑制情绪唤醒网络，导致增强内脏感知。的改变 循环肠道微生物代谢物，特别是色氨酸、雌激素和影响脑干的胆汁酸 核可能发挥额外的作用，和2）增加的患病率和严重程度的正常传输型便秘 在女性中（在运输或排便没有变化的情况下），是由于对正常，非 由中枢处理改变引起的结肠有害传入信号。这是由于广泛的 感觉运动、显著性和情绪唤醒网络的变化，部分与增加的输入有关 源自脑干核团的上行唤醒系统和上升活动的变化 来自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， 肠道微生物分类群丰度（16S rRNA）、总微生物基因含量（鸟枪宏基因组学）、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 连接和疼痛威胁诱发的反应）：1）比较GI症状和BGM 绝经前和绝经后女性IBS和健康对照（HC）的相互作用和2）比较 绝经前女性正常传输型便秘与慢传输型便秘及 HC。我们预计，我们的研究结果将确定新的内表型，可以导致发展的 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.