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: 10688180
• 负责人: JENNIFER S LABUS
• 金额: $ 23.07万
• 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/10688180
• 关键词: Abdominal Pain; Address; Afferent Pathways; Anatomy; Arousal; Behavioral; Bile Acids; Biological; Biological Markers; Brain; Brain Stem; Cell Nucleus; Characteristics; Chronic; Circulation; Classification; Clinical; Consensus; Data; Data Set; Databases; Development; Diagnostic Procedure; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Dorsal; Emotional; Enrollment; Estrogens; Female; Functional Imaging; 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; 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; Recurrence; Reporting; Research; Resolution; Rest; Role; Sensory; Sex Differences; Shotguns; Signal Transduction; Spinal; Stimulus; Stress; Structure; Symptoms; Testing; Tryptophan; Vertebral column; Volatile Fatty Acids; blood-brain barrier crossing; comorbidity; 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; structural imaging; 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.

抽象的 肠易激综合症（IBS）是一种非常普遍的肠道疾病，其特征是长期反复发作 腹痛和排便习惯改变。尽管过去几十年进行了广泛的研究工作，但 关于SABV的病理生理学、病理生理学中的作用尚未达成普遍共识，也没有任何研究 用于指导治疗决策的可靠生物标志物。这种缺乏进展反映在持续的 这些情况造成过多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失调的作用 IBS 中的脑肠微生物组 (BGM) 轴内。因此，本提案的总体目标是 确定不同脑干核团的性别特异性作用及其与多个大脑的双向相互作用 肠道网络、肠道微生物代谢物和女性性激素在 IBS 症状产生中的作用。 为了实现这一目标，我们将首先描述大脑中性别特异性功能和结构的变化， 在 IBS 患者和健康对照受试者中使用多模态 MRI（结构性、DTI、功能性 MRI）脑干 （HC）。我们将使用机器学习和神经网络方法来识别 CNS 签名 通过利用新注册的 IBS 受试者和我们现有的大型数据库来获取 IBS 的成像数据 IBS 和 HC 的功能和结构 MRI 扫描。我们将确定横截面中的性别差异 功能和结构成像测量、肠道微生物测量（RNA IBS 患者的测序、鸟枪法宏基因组学、代谢组学）和行为特征， 强调雌激素和色氨酸代谢物以及短链脂肪酸。收集到的信息来自 这项研究预计将确定基于生物学的男性和女性患者亚组，以揭示新的见解 BGM 相互作用在 IBS 病理生理学中的参与，特别是关于 BGM 相互作用的参与 脑干和肠道微生物代谢物，并帮助制定更有效的治疗策略 在肠易激综合征中。