GI Barrier and Microbiome Response to VSL3 in Irritable Bowel Syndrome

描述（由申请人提供）：全世界4 - 16岁的儿童中有10 - 46%患有复发性腹痛，其中高达66%的儿童在成年后发展为肠易激综合征（IBS）。来自成人的数据表明，运动障碍、内脏过敏、低级别胃肠道（GI）粘膜炎症和肠道细菌群的改变可能相互作用，产生IBS症状。某些益生菌如VSL#3可以改善这些因素，从而减少肠易激综合征的疼痛和大便症状。之前被允许进行前瞻性,随机,双盲试验的益生菌在儿童,FDA要求我们进行安全试验:# 3与IBS aduls下我们目前的印第安纳州。我们建议R34的支持将使我们能够执行额外的措施在成年人的安全试验,将促进我们最终推进的能力大,随机试验:# 3的儿童IBS关于剂量/持续时间药物动力学,通过提供信息肠道微生物组成，安全性，毒性和肠道屏障功能相关的益生菌的使用。因此，作为我们目前益生菌VSL#3在成人IBS患者中的安全性试验的一部分，我们的具体目标是：1)量化给药后粪便中VSL#3微生物特征的治疗持续时间/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；3)测量胃肠道通透性，作为给予不同治疗时间/ VSL#3总累积剂量前后肠道屏障功能的指标。该研究将按照FDA规定的安全性试验（IND# 13728）进行。将招募符合成人罗马III标准的IBS成人。病人

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.