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

摘要 肠易激综合征(IBS)和慢性正常传输便秘(CC)是常见的肠道疾病 这在女性中更为常见。此外，女性IBS患者在低雌激素期间会经历更多的疼痛 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的共识，没有令人满意的长期治疗，也没有可靠的 指导治疗决定的生物标志物。然而，越来越多的证据表明， 不同水平的脑-肠道微生物组(BGM)轴在IBS和IBS的病理生理学中起着核心作用 可能是抄送。这一建议基于女性性激素和肠道微生物的普遍假设 代谢产物在脑肠道微生物群相互作用中起着重要的调节作用，并且 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 感官处理功能导致对内脏和其他感官信号的感知增加， 功能性胃肠功能障碍患者的适应不良应对和共病焦虑特征。因此， 这项提案的总体目标是确定肠道微生物代谢物和雌激素对性别的特定影响 起源于不同脑干核团的上行觉醒通路上的水平改变活动和 参与症状产生的大脑网络的连通性。使用先进的大脑成像方法，Gut 微生物组分析，详细的临床表型分析，以及最新的统计和生物信息学 工具，这项提案在3个协同和密切相关的项目中解决了假设，并得到了 领导力管理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产物对女性IBS患者BGM相互作用的影响 黄体期和绝经后合并IBS和CC。项目2旨在清楚地识别脑干 核团产生上升的去甲肾上腺素能和5-羟色胺能投射到边缘和皮质脑区， 确定肠道微生物代谢物对这些唤醒系统的影响，并确定 男性和女性患者之间的这些影响。项目3旨在评估体内的生物机制 BGM轴在男女认知行为疗法临床疗效中的中介作用 IBS患者，并确定可能的预后预测因素和中介因素。从中获得的信息 研究可能揭示不同水平的大脑肠道微生物组轴参与IBS的新视角 病理生理学，并为确定最有效的治疗策略提供了强大的临床工具 患有功能性胃肠道疾病的女性和男性。

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.