Pathways to New Biomarkers in Recurrent Abdominal Pain in Children

描述(由申请人提供)：短语腹痛相关功能性胃肠(GI)紊乱(APFGIDs)已取代术语复发性腹痛，以描述一种疾病影响10%-46%的全球学龄儿童。它造成了巨大的经济、社会和情感负担，高达60%的儿童进入成年期。缺乏生物标记物来描述一种表型和随意定义的疾病的病理生理学特征，阻碍了治疗和治疗。我们建议研究新的GI和血清生物标记物，并使用心理社会痛苦的测量方法，我们的初步数据表明，APFGID儿童可能具有相当大的亚群特征。我们的研究还将为了解APFGID的病理生物学提供一个创新和重要的新机会。这些知识可能会导致更有效的管理和治疗策略。因此，在我们以前工作的基础上，我们提出了以下具体目标：1)比较7-12岁儿童的GI通透性和微生物群组成(GI生物标志物)。APFGIDs(n=150)与无腹痛的健康儿童(HC)(n=75)。假设-患有APFGIDs的儿童与HC相比有：H1)GI通透性增加，以及H2)GI微生物群富含Gammaproporteria和泽泻。2)在患有APFGIDs的儿童中，比较GI生物标志物异常与正常儿童的腹痛症状(频率/严重程度)和心理社会苦恼。假设-在APFGID儿童中，那些具有以下情况的儿童：H3)胃肠道通透性增加或H4)富含伽马蛋白细菌/泽泻的GI微生物组与通透性正常或微生物组组成正常的儿童相比，将出现更严重的腹痛症状，但较少出现心理社会痛苦。3)在同意抽血的儿童中(来自目标1的样本的70%-80%)，比较APFGID和HC儿童的血清免疫标记物(淋巴细胞和细胞因子)。次目标：探讨血清淋巴细胞和细胞因子谱的变化与APFGIDs儿童腹痛症状的关系。假设：H5)与HC相比，APFGID儿童CD19+/CD8+淋巴细胞减少/CD8+增加，血清促炎细胞因子比例增加；H6)在APFGID儿童中，免疫标志物改变的程度与腹痛症状相关。4)探索生物标志物之间的关联模式和亚群的分化。我们的多学科方法满足了NIH疼痛联盟和NINR的目标，以解决弱势群体(儿童)，这些人通常会成为患有慢性腹痛的成年人，并伴随着伴随而来的医疗费用(比健康高57%)。我们建议的研究很重要，因为与APFGID患者合作的卫生保健提供者面临挑战，因为潜在的病理生物学仍未明确，治疗并不普遍有效。我们的结果可能会将治疗范式从一刀切转向有针对性的管理(例如，针对胃肠道标志物异常和低心理社会痛苦的人使用益生菌)。 公共卫生相关性：根据来自世界各地的基于社区的研究，腹痛功能性胃肠疾病(APFGID)影响多达40%的儿童，并与重大的情感和经济负担有关。迫切需要了解在这些疾病中是什么因素导致疼痛，以便设计有效的管理和治疗策略。这项建议的结果将提供对腹痛症状的原因的洞察，以便更好地针对患者进行治疗。

DESCRIPTION (provided by applicant): The phrase abdominal pain-related functional gastrointestinal (GI) disorders (APFGIDs) has replaced the term recurrent abdominal pain to describe a condition affecting 10%-46% of school age children worldwide. It exerts a tremendous economic, social, and emotional burden and in up to 60% of children progresses into adulthood. Management and treatment are hampered by lack of biomarkers to characterize pathophysiologically what is a phenotypically and arbitrarily defined condition. We propose to study novel GI and serum biomarkers and use measures of psychosocial distress our preliminary data suggest likely characterize a substantial subset of children with APFGIDs. Our study also will provide an innovative and significant new opportunity to understand the pathobiology of APFGIDs. This knowledge likely will lead to more effective management and treatment strategies. Thus, building on our previous work, we propose the following SPECIFIC AIMS: 1) Compare GI permeability and microbiome composition (GI biomarkers) in children (7-12 yr. of age) with APFGIDs (n=150) vs. Healthy Children (HC) (n=75) without abdominal pain. Hypotheses - Children with APFGIDs vs. HC have: H1) Increased GI permeability and H2) A GI microbiome enriched with Gammaproteobacteria and Alistipes. 2) Among children with APFGIDs, compare abdominal pain symptoms (frequency/severity) and psychosocial distress in those with abnormal vs. normal GI biomarkers. Hypotheses - Among APFGID children, those with: H3) Increased GI permeability or H4) A GI microbiome enriched with Gammaproteobacteria/Alistipes will have greater abdominal pain symptoms but less psychosocial distress compared to those with normal permeability or microbiome composition. 3) In children who agree to have blood drawn (70-80% of the sample from Aim 1), compare serum immune markers (lymphocytes and cytokines) in children with APFGIDs versus HC. Sub-aim: explore how changes in serum lymphocytes and cytokine profiles relate to abdominal pain symptoms in children with APFGIDs. Hypotheses: H5) APFGID children will have decreased CD19+/increased CD8+ lymphocytes and an increased proportion of serum proinflammatory cytokines vs. HC; H6) In children with APFGIDs, the degree of immune marker alterations will correlate with abdominal pain symptoms. 4) Explore patterns of associations among biomarkers and differentiation of subgroups. Our multidisciplinary approach addresses NIH Pain Consortium and NINR goals to address a vulnerable population (children), who often go on to become adults with chronic abdominal pain with its attendant cost of medical care (57% greater vs. healthy). Our proposed study is important because health care providers working with patients with APFGIDs are challenged given the underlying pathobiology remains poorly defined and treatments are not universally effective. Our results could shift the paradigm of treatment from one-size-fits-all to targeted management (e.g., probiotics for those with abnormal GI markers and low psychosocial distress). PUBLIC HEALTH RELEVANCE: Abdominal pain functional gastrointestinal disorders (APFGIDs) affect up to 40% of children based on community based studies from around the world and are associated with significant emotional and economic burdens. There is a critical need to understand what factors contribute to pain in these disorders so that effective management and treatment strategies can be designed. The results of this proposal will provide insight into the factors responsible for abdominal pain symptoms to allow better patient-specific treatment.