GI Barrier and Microbiome Response to VSL3 in Irritable Bowel Syndrome

胃肠道屏障和微生物组对肠易激综合征中 VSL3 的反应

• 批准号: 8225753
• 负责人: Robert J Shulman
• 金额: $ 33.08万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8225753
• 关键词: Abdominal Pain; Accounting; Address; Adult; Adverse event; Affect; Age; Area; Bacteria; Child; Childhood; Communities; Data; Disease; Dose; Double-Blind Method; Drug Kinetics; Economic Burden; Emotional; Enteral; Feces; Future; Gastrointestinal Diseases; Habits; Health Care Visit; Hypersensitivity; Irritable Bowel Syndrome; Literature; Measures; Minority; Mucositis; NIH Program Announcements; National Center for Complementary and Alternative Medicine; Office Visits; Organism; Pain; Patients; Pattern; Performance; Permeability; Population; Probiotics; Questionnaires; Randomized; Recruitment Activity; Recurrence; Regulation; Research; Rome; Safety; Sampling; Seminal; Symptoms; Testing; Time; Toxic effect; United States; United States National Institutes of Health; Urine; Visceral; Work; base; cell motility; design; diaries; effective therapy; efficacy testing; experience; gastrointestinal; improved; insight; meetings; microbial; microbiome; open label; prospective; randomized trial; response; safety study; sugar; treatment duration; working group; Abdominal Pain; Accounting; Address; Adult; Adverse event; Affect; Age; Area; Bacteria; Child; Childhood; Communities; Data; Disease; Dose; Double-Blind Method; Drug Kinetics; Economic Burden; Emotional; Enteral; Feces; Future; Gastrointestinal Diseases; Habits; Health Care Visit; Hypersensitivity; Irritable Bowel Syndrome; Literature; Measures; Minority; Mucositis; NIH Program Announcements; National Center for Complementary and Alternative Medicine; Office Visits; Organism; Pain; Patients; Pattern; Performance; Permeability; Population; Probiotics; Questionnaires; Randomized; Recruitment Activity; Recurrence; Regulation; Research; Rome; Safety; Sampling; Seminal; Symptoms; Testing; Time; Toxic effect; United States; United States National Institutes of Health; Urine; Visceral; Work; base; cell motility; design; diaries; effective therapy; efficacy testing; experience; gastrointestinal; improved; insight; meetings; microbial; microbiome; open label; prospective; randomized trial; response; safety study; sugar; treatment duration; working group

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.

描述（由申请人提供）：10％至46％的儿童4-16岁。全世界的年龄复发性腹痛，其中有66％的成年人发展为肠易激综合症（IBS）。来自成年人的数据表明，运动性障碍，内脏超敏反应，低年级胃肠道（GI）粘膜炎症以及肠细菌种群的改变可能会相互作用以产生IBS的症状。某些益生菌（例如VSL＃3）可能会改善这些因素，从而减轻IBS的疼痛和粪便症状。在我们被允许在儿童中进行益生菌的前瞻性，随机，双盲试验之前，FDA要求我们在当前IND下对IBS进行VSL＃3的安全试验。我们建议R34的支持将使我们能够在成人安全试验中采取其他措施，从而有助于我们通过提供有关IBS儿童的大型，随机的VSL＃3试验，通过提供有关剂量/持续时间药代动力学的信息，肠道微生物微生物组成，安全性，毒性，毒性，毒性，以及与该概率相关的牙壳功能。因此，作为我们目前对益生菌VSL＃3的安全试验的一部分，在IBS患者中，我们的具体目的是：1）量化给药后粪便中VSL＃3中的生物体的微生物特征的总累积剂量反应； 2）确定VSL＃3给药对肠道微生物组整体组成的影响； 3）在给药不同处理持续时间之前和之后，测量gi渗透率作为肠道屏障功能的量度/VSL＃3的总累积剂量。该研究将根据我们的FDA强制安全试验（IND＃13728）进行。成年罗马三世标准定义的IB的成年人将被招募。患者 将使他们的疼痛和粪便习惯日记1周，在此期间，他们将收集基线粪便样品进行微生物分析并进行GI通透性尿糖测试。然后，他们将被随机地以开放标签的方式接收益生菌VSL＃3，其中包含9000亿个细菌的4周（n = 10）或8周（n = 10）。益生菌给药完成后，将重复粪便和GI通透性测试的微生物分析。在给药期间，益生菌患者将保持每天的疼痛和粪便日记以及任何不良事件。他们完成治疗后四个星期，他们将完成罗马三世问卷。拟议的研究介绍了第10杆163杆标识的优先领域以及一般NCCAM。我们的建议将提供有关不同治疗持续时间/VSL＃3累积剂量的影响的初步数据，该细菌在VSL＃3中的肠道化以及它们对GI屏障功能（渗透性）的影响对于计划和对IBS的儿童进行大型，随机试验的概念性试验至关重要。更远， 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对儿童研究VSL＃3研究的要求至关重要。 公共卫生相关性：肠易激综合征影响10-15％的成人和儿童，并与巨大的身体，情感和经济负担有关。有效疗法的迫切需要。该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衰弱的疾病方面有希望。