Sex -related differences in structure, function and connectivity of central arousal and salience networks involving brainstem nuclei are involved in IBS symptom generation.

涉及脑干核的中枢唤醒和显着网络的结构、功能和连接性方面的性别相关差异参与了 IBS 症状的产生。

• 批准号: 10461218
• 负责人: JENNIFER S LABUS
• 金额: $ 23.09万
• 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/10461218
• 关键词: Abdominal Pain; Address; Afferent Pathways; Aging; Anatomy; Arousal; Behavioral; Bile Acids; Biological; Biological Markers; Blood - brain barrier anatomy; Blood Circulation; Brain; Brain Stem; Cell Nucleus; Characteristics; Chronic; Classification; Clinical; Consensus; Data; Data Set; Databases; Development; Diagnostic Procedure; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Dorsal; Emotional; Enrollment; Estrogens; Female; Functional Magnetic Resonance Imaging; Functional disorder; Generations; Goals; Habits; Health Care Costs; Hypersensitivity; Image; Imaging Techniques; Imaging technology; Intestinal Diseases; Intestines; Investigation; Irritable Bowel Syndrome; Kynurenine; Laboratories; Lead; MRI Scans; Machine Learning; Magnetic Resonance Imaging; Measurable; Measurement; Measures; Metagenomics; Multimodal Imaging; Neuronal Plasticity; Pain; Pathway interactions; Patients; Physiological; Plasma; Play; Pontine structure; Property; Public Health; Reporting; Research; Resolution; Rest; Role; Sensory; Sex Differences; Shotguns; Signal Transduction; Spinal; Stress; Structure; Symptoms; Testing; Tryptophan; Volatile Fatty Acids; base; drug development; effective therapy; expectation; female sex hormone; gut microbiome; insight; learning network; male; metabolomics; microbial; multimodality; neural network; neuromelanin; novel; patient subsets; personalized intervention; recruit; sex; transcriptome sequencing; treatment strategy

ABSTRACT Irritable bowel syndrome (IBS) is a highly prevalent intestinal disorder characterized by chronically recurring abdominal pain and altered bowel habit. Despite extensive research efforts over the past few decades, there is no general consensus about the pathophysiology, the role of SABV in pathophysiology, nor are there been any reliable biomarkers for guiding treatment decisions. This lack of progress is reflected in the continued excessive direct and indirect health care costs generated by these conditions, largely due to unnecessary diagnostic procedures and lack of effective therapies. Increasing evidence supports a role of dysregulations within the brain-gut microbiome (BGM) axis in IBS. Therefore, the overall goal of this proposal is to determine the sex-specific role of distinct brainstem nuclei and their bidirectional interactions with several brain networks, of the gut, and of gut microbial metabolites and female sex hormones in symptom generation in IBS. To address this goal we will first characterize sex-specific functional and structural changes in the brain and brainstem using multimodal MRI (structural, DTI, functional MRI) in IBS patients and healthy control subjects (HCs). We will use machine learning and neural network approaches to identify a CNS signature from the imaging data for IBS by leveraging both the newly enrolled IBS subjects and our large existing database of functional and structural MRI scans in IBS and HCs. We will identify sex differences in cross sectional associations between functional and structural imaging measurements, gut microbial measures (RNA sequencing, shotgun metagenomics, metabolomics) and behavioral characteristics of IBS patients, with an emphasis on estrogen and tryptophan metabolites and short chain fatty acids. The information garnered from this study is expected to identify biologically based male and female patient subgroups, to reveal novel insights into the involvement of BGM interactions in IBS pathophysiology, in particular about the involvement of the brainstem and gut microbial metabolites, and to aid in the development of more effective treatment strategies in IBS.

摘要 肠易激综合征(IBS)是一种以慢性复发为特征的高度流行的肠道疾病。 腹痛和排便习惯改变。尽管在过去的几十年里做出了广泛的研究努力，但有 关于SABV的病理生理学、SABV在病理生理学中的作用没有普遍的共识，也没有任何 指导治疗决策的可靠生物标志物。这种缺乏进展的情况反映在持续的 这些情况产生的过高的直接和间接医疗费用，主要是由于不必要的 诊断程序和缺乏有效的治疗方法。越来越多的证据支持监管失调的作用 在IBS的脑-肠道微生物组(BGM)轴内。因此，这项提案的总体目标是 确定不同脑干核团的性别特异性作用及其与几个脑的双向相互作用 肠易激综合征症状发生过程中肠道、肠道微生物代谢产物和女性性激素的网络。 为了解决这一目标，我们将首先表征大脑和大脑中特定性别的功能和结构变化 IBS患者和健康对照组脑干多模式磁共振成像(结构、DTI、功能MRI)研究 (HCS)。我们将使用机器学习和神经网络方法从 通过利用新登记的IBS受试者和我们现有的大型数据库来为IBS成像数据 IBS和HCS的功能和结构MRI扫描。我们将在横截面中识别性别差异 功能和结构成像测量、肠道微生物测量(RNA)之间的关联 测序、鸟枪式元基因组学、代谢组学)和IBS患者的行为特征 重点是雌激素和色氨酸代谢物和短链脂肪酸。从以下渠道获得的信息 这项研究有望确定基于生物学的男性和女性患者亚组，以揭示新的见解 探讨BGM相互作用在IBS病理生理学中的作用，特别是关于BGM的作用 脑干和肠道微生物代谢物，并帮助制定更有效的治疗策略 在IBS。