Microbiome and Pain in IBS

描述（由申请人提供）：大约10-20%的成年人出现慢性腹部症状（腹痛/不适和相关的肠道变化[便秘和/或腹泻]），与肠易激综合征（IBS）的诊断相符。在美国和其他西方国家，女性寻求医疗保健服务的比例高于男性。IBS的定义是慢性腹痛/不适，伴有肠道模式改变（腹泻、便秘或两者兼而有之[混合]）。在美国，IBS对公共卫生的影响是巨大的，直接和间接成本总计约60亿美元/年。研究表明，胃肠道（GI）通透性增加（“漏肠”）、肠粘膜组成异常、肠粘膜上皮细胞和肠上皮细胞之间存在相互作用。 GI微生物组（定义为细菌，其基因组和与宿主的相互作用），免疫反应改变，自主神经功能障碍（高交感神经张力）和心理社会困扰导致IBS的症状和随后的功能影响。我们的长期目标是描述病理生物学和心理社会困扰的贡献，以更好地为患者管理提供信息，例如，饮食与认知行为方法）。我们建议比较患有IBS和没有IBS的女性的GI微生物群，肠道通透性，细胞因子以及GI和心理困扰症状。我们还将获得关于没有异常GI标志物证据的IBS女性的重要信息。目前的提案还将使我们能够定义与症状相关的微生物组组成和病理生理学特征，以及可能的病因。因此，第一个具体目标是比较女性（18-45岁）的GI微生物组、渗透性和细胞因子。年龄组）与IBS（n=100）对比无IBS的健康对照（HC）（n=50）。基于儿科数据，我们假设在患有IBS的女性中，具有富含变形菌门/肠杆菌科的GI微生物群、GI渗透性增加或细胞因子水平增加的那些女性与没有这种富含变形菌门/肠杆菌科的微生物群组成、正常渗透性或较低细胞因子水平的那些女性相比将具有更大的腹痛症状。第二个目的是比较胃肠道生物标志物异常与正常的IBS受试者中的腹痛、其他IBS症状和心理社会困扰症状。此外，我们将探讨胃肠道生物标志物之间的关联模式，以及胃肠道生物标志物与腹痛和其他症状的关联模式。目标是根据生物标志物确定可能的IBS亚组。这项研究是创新的，因为我们将使用生物标志物（例如，GI微生物组分析、渗透性和血清标志物应用新奇性来表征迄今为止主要是表型和任意定义的病症的病理生物学特征。我们将整合心理社会因素（例如，焦虑，躯体化，共病功能状况），我们的初步数据表明，可能是占主导地位的一些妇女与IBS。

DESCRIPTION (provided by applicant): Approximately 10-20% of adults experience chronic abdominal symptoms (abdominal pain/discomfort and associated bowel changes [constipation and/or diarrhea] compatible with a diagnosis of irritable bowel syndrome (IBS). In the US as well as other western countries, women seek health care services disproportionately to men. IBS is defined as chronic abdominal pain/discomfort accompanied by altered bowel pattern (diarrhea, constipation or both [mixed]). The public health impact of IBS in the US is enormous with direct and indirect costs totaling approximately $6 billion/year. Studies suggest an interplay between increased gastrointestinal (GI) permeability ('leaky gut'), abnormalities in the composition of the GI microbiome (defined as bacteria, their genomes and interaction with the host), altered immune responses, autonomic dysfunction (high sympathetic tone), and psychosocial distress lead to the symptoms and the subsequent functional impact of IBS. Our long term goal is to delineate the contribution of pathobiology and psychosocial distress to better inform patient management e.g., diet versus cognitive behavioral approaches). We propose to compare GI microbiota, intestinal permeability, cytokines, and GI and psychological distress symptoms in menstruating women with IBS and without IBS. We also will derive important information about women with IBS with no evidence of abnormal GI markers. The current proposal will also allow us to define microbiome composition and pathophysiological features tied to symptoms, and likely etiology. Thus, the first specific aim is to compare GI microbiome, permeability and cytokines in women (18-45 yr. of age) with IBS (n=100) vs. Healthy Controls (HC) (n=50) without IBS. Based on pediatric data, we hypothesize that among women with IBS, those with a GI microbiome enriched with Proteobacteria/Enterobacteriaceae, increased GI permeability or increased cytokine levels will have greater abdominal pain symptoms versus those without this Proteobacteria/Enterobacteriaceae enriched microbiota composition, normal permeability, or lower cytokine levels. The second aim will be to compare abdominal pain, other IBS symptoms and psychosocial distress symptoms in those IBS subjects with abnormal versus normal GI biomarkers. In addition we will explore patterns of associations among GI biomarkers, and of GI biomarkers with abdominal pain and other symptoms. The goal is to identify possible IBS subgroups based on biomarkers. This research is innovative because we will use biomarkers (e.g., GI microbiome analyses, permeability, and serum markers applied novelty to characterize pathobiologically what heretofore has been primarily a phenotypically and arbitrarily defined condition. We will integrate psychosocial factors (e.g., anxiety, somatization, co-morbid functional conditions) that our preliminary data suggest are likely to predominate in some women with IBS.