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Sex related differences in Brain Gut Microbiome Interactions in Irritable Bowel Syndrome

肠易激综合症中脑肠微生物组相互作用的性别相关差异

基本信息

批准号：
10688165
负责人：
Lin Chang
金额：
$ 124.67万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
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/10688165
关键词：
Address Affective Anatomy Anxiety Arousal Bile Acids Biological Biological Markers Brain Brain Stem Brain imaging Brain region Cell Nucleus Characteristics Chronic Chronic Disease Clinical Clinical effectiveness Cognitive Cognitive Therapy Consensus Constipation Data Analyses Diffusion Digestive System Disorders Disease Doctor of Philosophy Effectiveness Emotional Estrogen decline Estrogens Female Functional Gastrointestinal Disorders Functional disorder Funding Gastrointestinal Diseases Generations Goals Gonadal Steroid Hormones Image Intestinal Diseases Irritable Bowel Syndrome Leadership Luteal Phase Mediating Mediator Menopause Menstruation Outcome Pain Pathway interactions Patients Perception Physiological Play Pontine structure Postmenopause Premenopause Prevalence Progress Reports Public Health Publications Reproducibility Research Research Personnel Rest Role Sensory Severities Sex Differences Signal Transduction Structure Subgroup Symptoms System Treatment Effectiveness Treatment outcome Tryptophan Visceral Volatile Fatty Acids Woman bioinformatics tool career clinical phenotype comorbidity computerized data processing coping experience female sex hormone gut microbiome gut-brain axis imaging modality improved insight male men microbial microbiome analysis neuromelanin noradrenergic novel response sex therapeutically effective therapy outcome tool treatment response treatment strategy

项目摘要

ABSTRACT Irritable bowel syndrome (IBS) and chronic normal transit constipation (CC) are prevalent intestinal disorders which are more common in women. In addition, female IBS patients experience more pain during low estrogen states, e.g. during the luteal phase of the menstrual period and post menopause. Until recently, there was no consensus about the pathophysiology of these disorders, no satisfactory long term treatments, and no reliable biomarkers for guiding treatment decisions. However, there is increasing evidence that disturbances at different levels of the brain-gut microbiome (BGM) axis play a central role in the pathophysiology of IBS and possibly CC. This proposal is based on the general hypothesis that female sex hormones and gut microbial metabolites play an important modulatory role on brain gut microbiome interactions, and that ascending arousal systems originating in the brainstem may in part responsible for the altered cognitive, affective and sensory processing function resulting in increased perception of visceral and other sensory signals, maladaptive coping, and comorbid anxiety characteristic for patient with functional GI disorders. Therefore, the overall goal of this proposal is to identify the sex-specific effect of gut microbial metabolites, and estrogen levels on ascending arousal pathways originating in distinct brainstem nuclei to change the activity and connectivity of brain networks involved in symptom generation. Using advanced brain imaging methods, gut microbiome analyses, and detailed clinical phenotyping, as well as state of the art statistical and bioinformatics tools, this proposal is addressing the hypothesis in 3 synergistic and closely related Projects, assisted by a Leadership Administrative Core and a Data Processing and Analysis Core. Project 1 aims to study the influence of natural low estrogen states and microbial metabolites on BGM interactions in female IBS patients with IBS and CC in the luteal phase, and after menopause. Project 2 aims to clearly identify the brainstem nuclei giving rise to ascending noradrenergic and serotonergic projections to limbic and cortical brain regions, determine the influence of gut microbial metabolites on these arousal systems and determine differences in these effects between male and female patients. Project 3 aims to evaluate the biological mechanisms within the BGM axis that mediate the clinical effectiveness of cognitive behavioral therapy (CBT) in male and female IBS patients, and identify possible predictors and mediators of outcome.The information garnered from this study could reveal novel insight into the involvement of different levels of the brain gut microbiome axis in IBS pathophysiology, and provide a powerful clinical tool for identifying the most effective therapeutic strategies for women and men with functional GI disorders.

抽象的肠易激综合征 (IBS) 和慢性正常传输性便秘 (CC) 是常见的肠道疾病这在女性中更常见。此外，女性 IBS 患者在雌激素水平较低时会经历更多疼痛州，例如在月经期的黄体期和绝经后。直到最近，还没有关于这些疾病的病理生理学达成共识，没有令人满意的长期治疗方法，也没有可靠的方法指导治疗决策的生物标志物。然而，越来越多的证据表明，不同水平的脑肠微生物组 (BGM) 轴在 IBS 的病理生理学中发挥着核心作用，可能是CC。该提议基于以下一般假设：女性性激素和肠道微生物代谢物对脑肠道微生物组相互作用起着重要的调节作用，并且上升起源于脑干的唤醒系统可能在一定程度上导致了认知、情感和情感的改变。感觉处理功能导致内脏和其他感觉信号的感知增强，功能性胃肠道疾病患者的适应不良应对和共病焦虑特征。因此，该提案的总体目标是确定肠道微生物代谢物和雌激素的性别特异性效应源自不同脑干核的上升唤醒通路的水平，以改变活动和参与症状产生的大脑网络的连接性。使用先进的大脑成像方法，肠道微生物组分析、详细的临床表型分析以及最先进的统计和生物信息学工具，该提案正在解决 3 个协同且密切相关的项目中的假设，并得到了领导行政核心和数据处理和分析核心。项目1旨在研究自然低雌激素状态和微生物代谢物对女性 IBS 患者 BGM 相互作用的影响黄体期和绝经后患有 IBS 和 CC。项目2旨在清晰识别脑干核产生上升的去甲肾上腺素能和血清素能投射到边缘和皮质大脑区域，确定肠道微生物代谢物对这些唤醒系统的影响并确定这些影响在男性和女性患者之间。项目3旨在评估其中的生物学机制调节男性和女性认知行为治疗 (CBT) 临床效果的 BGM 轴 IBS 患者，并确定结果的可能预测因素和中介因素。从中收集的信息研究可能揭示大脑肠道微生物组轴不同水平参与肠易激综合症的新见解病理生理学，并为确定最有效的治疗策略提供强大的临床工具患有功能性胃肠道疾病的女性和男性。