GI Barrier and Microbiome Response to VSL3 in Irritable Bowel Syndrome

描述(申请人提供)：4-16岁儿童的比例为10%至46%。世界各地的老年人反复腹痛，其中高达66%的人成年后会患上肠易激综合征(IBS)。来自成人的数据表明，动力障碍、内脏超敏反应、低度胃肠(GI)粘膜炎症和肠道细菌群的变化可能相互作用而产生IBS症状。某些益生菌，如VSL#3，可能会改善这些因素，从而减轻IBS的疼痛和大便症状。在我们被允许进行儿童益生菌的前瞻性、随机、双盲试验之前，FDA要求我们在我们目前的IND下对患有IBS的成年人进行VSL#3的安全性试验。我们认为，R34的支持将使我们能够在成人安全试验中采取额外的措施，通过提供与使用这种益生菌相关的剂量/持续时间、肠道微生物组成、安全性、毒性和肠道屏障功能的信息，最终推动VSL#3在患有IBS的儿童中的大规模随机试验。因此，作为我们目前针对成年IBS患者进行的益生菌VSL#3安全性试验的一部分，我们的具体目标是：1)量化治疗持续时间/VSL#3给药后粪便中细菌的总累积剂量反应；2)确定VSL#3给药对肠道微生物群总体组成的影响；以及3)测量VSL#3在给药不同时间前后的GI通透性作为衡量肠道屏障功能的指标/VSL#3的总累积剂量。该研究将按照FDA规定的安全试验(IND#13728)进行。将招募患有罗马III成人标准所定义的IBS的成年人。病人 将记录他们的疼痛和大便习惯一周，在此期间，他们将收集基线粪便样本进行微生物分析，并接受胃肠道通透性尿糖测试。然后，他们将被随机接受以开放标签方式接受含有9000亿个细菌的益生菌VSL#3，试验时间为4wk(n=10)或8wk(n=10)。在服用益生菌完成后，将重复进行粪便微生物分析和胃肠道通透性试验。在服用益生菌期间，患者将记录每天的疼痛和排便日记，并记录任何不良事件。在他们完成治疗四周后，他们将完成罗马III问卷调查。拟议的研究涉及PAR-10-163以及NCCAM总体上确定的优先领域。我们的提案将提供有关VSL#3不同治疗时间/累积剂量对VSL#3中细菌在肠道定植的影响以及它们对胃肠道屏障功能(通透性)的影响的初步数据，这将是计划和进行针对IBS儿童的益生菌的大型随机试验的关键。此外， 我们的结果将提供有关VSL#3的安全性和潜在毒性的关键信息，这对于满足FDA对儿童VSL#3研究的IND要求至关重要。 公共卫生相关性：肠易激综合征影响10%-15%的成人和儿童，并与重大的身体、情感和经济负担有关。迫切需要有效的治疗方法。这项提案的结果将提供在儿童中设计和执行VSL#3的随机双盲试验所需的关键信息。VSL#3是一种益生菌，在治疗这种经常使人虚弱的疾病方面显示出了希望。

DESCRIPTION (provided by applicant): Ten to 46% of children 4 - 16 yr. of age around the world have recurrent abdominal pain and up to 66% of these develop irritable bowel syndrome (IBS) as adults. Data from adults suggest that motility disturbances, visceral hypersensitivity, low grade gastrointestinal (GI) mucosal inflammation, and alterations in the enteric bacterial population may interact with each other to produce the symptoms of IBS. Certain probiotics such as VSL#3 may act to improve these factors and thus, reduce the pain and stooling symptoms of IBS. Before we are permitted to carry out a prospective, randomized, double-blind trial of probiotics in children, the FDA requires that we carry out a safety trial of VSL#3 in aduls with IBS under our current IND. We propose that R34 support will enable us to carry out additional measures in the adult safety trial that will facilitate our ability to eventually move forward with a large, randomized trial of VSL#3 in children with IBS by providing information regarding dose/duration pharmacokinetics, gut microbial composition, safety, toxicity, and gut barrier function related to the use of this probiotic. Thus, as part of our current safety trial ofthe probiotic VSL#3 in adult patients with IBS our Specific Aims are to: 1) Quantify the duration of treatment/total cumulative dose response of microbial signatures of the organisms in VSL#3 in stool after administration; 2) Determine the effect of VSL#3 administration on the overall composition of the gut microbiome; and 3) Measure GI permeability as a measure of gut barrier function before and after the administration of different durations of treatments/total cumulative dose of VSL#3. The study will be carried out in accordance with our FDA mandated safety trial (IND# 13728). Adults with IBS as defined by the adult Rome III criteria will be recruited. Patients will keep a diary of their pain and stooling habits for 1 week during which time they will collect baseline stool sample for microbial analysis and undergo a GI permeability urine sugar test. They then will be randomized to receive in an open-label fashion the probiotic VSL#3 containing 900 billion bacteria for either 4 wk (n=10) or 8 wk (n=10). The microbial analysis of stool and GI permeability test will be repeated after completion of probiotic administration. During administration of the probiotic patients will keep a daily pain and stooling diary as well as recor any adverse events. Four weeks after they have finished the treatment they will complete the Rome III questionnaire. The proposed study addresses priority areas identified by PAR-10-163 as well as NCCAM in general. Our proposal will provide preliminary data on the effects of different durations of treatment/cumulative doses of VSL#3 on colonization of the gut by the bacteria in VSL#3 and their effect on GI barrier function (permeability) that will be crucial in planning and carrying out a large, randomized trial of the probiotic in children with IBS. Further, our results will provide critical information regarding the safety and potential toxicity of VSL#3 that will be vital to satisfying FDA requirements for an IND for the study of VSL#3 in children. PUBLIC HEALTH RELEVANCE: Irritable bowel syndrome affects 10-15% of adults and children and is associated with significant physical, emotional, and economic burdens. There is a critical need for effective therapies. The results of this proposal will provide key information required to design and carry out in children a randomized double-blind trial of VSL#3, a probiotic that has shown promise in the treatment of this often debilitating disorder.