Omics and Variable Responses to Placebo and Acupuncture in Irritable Bowel Syndro

肠易激综合征（IBS）是一种慢性疾病，影响工业化国家10-15%的人口。IBS与患者生活质量的严重损害、生产力的显著损失以及仅在美国的20亿美元的直接医疗保健成本相关，主要是由于不满意的治疗。患者在疾病发病机制、症状表现和心理共病方面的异质性是影响治疗反应变化的因素之一。因此，必须开发生物标记物，以区分可能从特定形式的治疗中获益最多的患者，同样重要的是，从安慰剂治疗中获益最多的患者。我们最近完成了一项在IBS患者（n=262）中进行的为期6周的随机临床试验，以检查安慰剂和针灸治疗与自然史对照组相比的效果。在基线和随访3周和6周时采集血样。该试验的积极结果和样本可用性使我们能够进行二次组学分析，检查患者对治疗的反应差异。我们的主要假设是，血清蛋白直接或间接参与脑肠相互作用与临床反应在IBS。我们的第二个假设是，临床上对安慰剂或针灸治疗有反应的患者与那些没有反应的患者有不同的血清蛋白质谱。第三个假设是安慰剂或针灸治疗导致血清蛋白质组的变化。我们将采用各种高通量实验方法，其中一些针对特定的生物学途径，另一些则导致无偏见的发现，以实现本研究的目标。血清蛋白质组学分析将与出现的感兴趣基因中常见多态性的调查相补充。这些研究的结果可能会导致基于生物筛选的随机临床试验中纳入/排除标准的改进。在个性化医疗方面，研究结果可能会导致提高药物反应，调整剂量或选择副作用较少的药物的方法。 公共卫生相关性：使用身心机制（包括安慰剂效应）的自我愈合可以对医疗保健产生重大影响，尽管生物过程的定义和理解很差。在之前NIH资助的262例肠易激综合征（IBS）患者的临床研究中，一种影响高达15%的美国人口的胃肠道疾病，我们发现安慰剂治疗，通过支持性患者-医生互动增强，可以显着改善这些患者的临床症状和整体生活质量。这项研究还表明，针灸对某些患者有潜在的好处。目前的应用是对初始研究期间采集的血液样本进行二次随访分析。我们将使用高通量方法（组学）和生物信息学来确定安慰剂和针灸治疗的各种身心效应的生物标志物。我们的第二个目标是生成一个生物特征，可以用来预测那些对这种非药物治疗有反应的人和那些没有反应的人。我们的发现将改善临床试验的设计，并有助于“个性化”医学的实践。

DESCRIPTION (provided by applicant): Irritable bowel syndrome (IBS) is a chronic medical condition which affects 10-15% of the population in industrialized countries. IBS is associated with a profound impairment of patient's quality of life, significant loss of productivity, and $2 billion in direct health care costs in the US alone, mainly due to unsatisfactory treatment. Patient heterogeneity in terms of disease pathogenesis, symptom expression and psychological co-morbidities are among the factors implicated in the variation of therapeutic responses. Therefore, the need to develop biological markers that can distinguish patients likely to benefit most from specific forms of treatment, and as importantly, from a placebo treatment, is imperative. We have recently concluded a 6 week randomized clinical trial in IBS patients (n=262) to examine the effects of placebo and acupuncture treatments, compared to a natural history control group. Blood samples were collected at baseline and at 3 and 6 weeks of follow-up. The positive results of this trial and sample availability allow us to perform a secondary Omics analysis examining patient variability in response to treatment. Our primary hypothesis is that serum proteins participate directly or indirectly to the brain-gut interactions associated with clinical responses in IBS. Our second hypothesis is that patients who clinically respond to placebo or acupuncture treatment have distinct serum protein profiles from those who don't respond. A third hypothesis is that placebo or acupuncture treatment results in changes in the serum proteome. We will incorporate various high throughput experimental approaches, some of them targeted to specific biological pathways and others leading to unbiased discoveries, to pursue the goals of this study. The serum proteomics analysis will be complemented with an investigation of common polymorphisms in genes of interest that emerge. Findings stemmed from such studies could lead to improvement of inclusion/exclusion criteria in randomized clinical trials based on biological screens. In terms of personalized medicine, findings could result in methodologies to enhance medication responses, adjust the doses or select medications with fewer side effects. PUBLIC HEALTH RELEVANCE: Self healing using mind-body mechanisms, including placebo effects, can have a major impact on health care, though the biological process is poorly defined and understood. In a previous NIH-funded clinical study of 262 patients with irritable bowel syndrome (IBS), a gastrointestinal disease that affects up to 15% of the US population, we showed that placebo treatment, augmented by a supportive patient-practitioner interaction, could dramatically improve clinical symptoms and overall quality of life in those patients. The same study also indicated that acupuncture has potential benefit for some patients. The current application is a secondary, follow- up analysis of blood samples collected during the initial study. We will use high throughput approaches (Omics) and bioinformatics to identify biological markers for the various mind-body effects of placebo and acupuncture treatments. Our second goal is to generate a biological signature which can be used to predict individuals who respond and those who do not to such non-pharmacological treatments. Our findings will improve the design of clinical trials and contribute to the practice of "personalized" medicine.