Pathways to New Biomarkers in Recurrent Abdominal Pain in Children

描述（由申请人提供）：术语腹痛相关功能性胃肠道（GI）疾病（apfgid）已取代术语复发性腹痛来描述影响全球10%-46%学龄儿童的疾病。它带来了巨大的经济、社会和情感负担，高达60%的儿童会成长为成年人。管理和治疗由于缺乏生物标志物来表征病理生理特征而受到阻碍，这是一种表型和任意定义的疾病。我们建议研究新的GI和血清生物标志物，并使用社会心理困扰的测量方法，我们的初步数据表明可能表征apfgid患儿的很大一部分。我们的研究也将为理解apfgid的病理生物学提供一个创新和重要的新机会。这一知识可能会导致更有效的管理和治疗策略。因此，在我们之前工作的基础上，我们提出以下具体目标：1)比较患有apfgid的儿童（7-12岁）（n=150）和没有腹痛的健康儿童（HC） （n=75）的胃肠道通透性和微生物组组成（GI生物标志物）。假设-患有APFGIDs与HC的儿童有：H1)胃肠道通透性增加，H2)胃肠道微生物群富含γ变形菌和阿里斯特菌。2)在患有APFGIDs的儿童中，比较GI生物标志物异常与正常的儿童的腹痛症状（频率/严重程度）和社会心理困扰。假设-在APFGID儿童中，与渗透性或微生物组成正常的儿童相比，具有：H3)胃肠道通透性增加或H4)胃肠道微生物群富含γ变形菌/Alistipes的儿童将有更大的腹痛症状，但更少的心理社会困扰。3)在同意抽血的儿童（来自Aim 1的70-80%样本）中，比较APFGIDs患儿与HC患儿的血清免疫标记物（淋巴细胞和细胞因子）。亚目的：探讨血清淋巴细胞和细胞因子谱的变化与APFGIDs患儿腹痛症状的关系。假设：H5)与HC相比，APFGID患儿CD19+/ CD8+淋巴细胞减少/ CD8+淋巴细胞增加，血清促炎因子比例增加；H6)在apfgid患儿中，免疫标记物改变的程度与腹痛症状相关。4)探索生物标志物与亚群分化之间的关联模式。我们的多学科方法解决了NIH疼痛联盟和NINR的目标，即解决弱势群体（儿童），他们通常会在成年后患上慢性腹痛，并伴随医疗费用（比健康人群高出57%）。我们提出的研究很重要，因为医疗保健提供者与apfgid患者的工作面临挑战，因为潜在的病理生物学仍然不明确，治疗方法也不是普遍有效。我们的研究结果可以将治疗模式从“一刀切”转变为有针对性的管理（例如，对那些有异常胃肠道标志物和低社会心理困扰的人使用益生菌）。

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.