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

摘要 肠易激综合征（IBS）是一种高度流行的肠道疾病， 腹痛和排便习惯改变尽管在过去几十年中进行了广泛的研究， 关于病理生理学，SABV在病理生理学中的作用，没有普遍的共识，也没有任何 用于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， 过度的直接和间接的医疗保健费用产生的这些条件，主要是由于不必要的 诊断程序和缺乏有效的治疗。越来越多的证据支持失调的作用 在IBS的脑肠道微生物组（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几个脑的双向相互作用 网络，肠道，肠道微生物代谢产物和女性性激素在IBS症状的产生。 为了实现这一目标，我们将首先描述大脑中性别特异性的功能和结构变化， 在IBS患者和健康对照受试者中使用多模式MRI（结构、DTI、功能MRI）对脑干进行研究 （HC）。我们将使用机器学习和神经网络方法来识别CNS签名， 通过利用新入组的IBS受试者和我们现有的大型IBS数据库， IBS和HC的功能和结构MRI扫描。我们将确定横截面的性别差异， 功能和结构成像测量之间的关联，肠道微生物测量（RNA 基因测序、鸟枪宏基因组学、代谢组学）和行为特征， 强调雌激素和色氨酸代谢物和短链脂肪酸。信息收集自 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 脑干和肠道微生物代谢产物，并帮助开发更有效的治疗策略 在IBS。

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.