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）疾病（APFGID）已取代术语复发性腹痛，用于描述影响全球10%-46%学龄儿童的疾病。它产生了巨大的经济，社会和情感负担，高达60%的儿童进入成年期。缺乏生物标志物来表征病理生理学上的表型和任意定义的病症，这阻碍了管理和治疗。我们建议研究新的胃肠道和血清生物标志物，并使用心理社会困扰的措施，我们的初步数据表明可能表征APFGID儿童的一个重要子集。我们的研究还将为了解APFGIDs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）比较儿童（7-12岁）的GI渗透性和微生物组组成（GI生物标志物）。APFGID组（n=150）与无腹痛的健康儿童（HC）组（n=75）。假设-患有APFGID的儿童与患有HC的儿童相比具有：H1）GI渗透性增加和H2）富含γ-变形菌和Alistipes的GI微生物组。2)在APFGID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）和心理社会困扰。假设-在APFGID儿童中，与具有正常渗透性或微生物组组成的儿童相比，具有H3）GI渗透性增加或H4）富含γ-变形菌/Alistipes的GI微生物组的儿童将具有更大的腹痛症状，但较少的心理社会困扰。3)在同意抽血的儿童中（目标1样本的70-80%），比较APFGID与HC儿童的血清免疫标志物（淋巴细胞和细胞因子）。子目的：探讨血清淋巴细胞和细胞因子谱的变化如何与APFGID儿童的腹痛症状相关。假设：H5）与HC相比，APFGID儿童将具有降低的CD 19 +/增加的CD 8+淋巴细胞和增加的血清促炎细胞因子比例; H6）在患有APFGID的儿童中，免疫标志物改变的程度将与腹痛症状相关。4)探索生物标志物和亚组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，以解决弱势群体（儿童），他们经常继续成为慢性腹痛的成年人，伴随着医疗费用（比健康人高57%）。我们提出的研究很重要，因为与APFGID患者一起工作的医疗保健提供者面临挑战，因为潜在的病理生物学仍然定义不清，治疗并不普遍有效。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，益生菌用于那些具有异常GI标志物和低心理社会困扰的人）。 公共卫生相关性：根据来自世界各地的基于社区的研究，腹痛功能性胃肠道疾病（APFGID）影响高达40%的儿童，并与显著的情感和经济负担相关。有一个关键的需要，以了解哪些因素有助于这些疾病的疼痛，以便有效的管理和治疗策略可以设计。该提案的结果将提供对腹痛症状的因素的深入了解，以便更好地进行患者特异性治疗。

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.