VSL for Asthma

VSL 治疗哮喘

• 批准号: 7807082
• 负责人: Alessio Fasano
• 金额: $ 14.85万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7807082
• 关键词: 17 year old; Address; Adherence; Adult; Affect; Age; Allergens; Allergic; Alternative Therapies; American; Antibiotics; Antigens; Applications Grants; Asthma; Bacteria; Bifidobacterium; Biological Markers; Breathing; Cells; Child; Childhood; Chronic; Chronic Disease; Clinical; Clinical Research; Collection; Complementary and alternative medicine; Consumption; Controlled Clinical Trials; Coughing; Data; Development; Diagnosis; Diet; Disease; Dose; Down-Regulation; Dyspnea; Enrollment; Equilibrium; Exercise; Exploratory/Developmental Grant; Feces; Food Hypersensitivity; Frequencies; Future; Gastrointestinal Diseases; Gastrointestinal tract structure; Goals; Grant; Health; Health Care Visit; Health Food; Hour; Hypersensitivity; Immune; Immune Tolerance; Immune response; Immune system; Individual; Inflammation; Ingestion; Interleukin-10; Interleukin-13; Interleukin-4; Interleukin-5; Intestinal Diseases; Intestines; Knowledge; Lactobacillus; Lactulose; Lead; Lung; Mannitol; Measurable; Measures; Medical; Microbe; National Center for Complementary and Alternative Medicine; Organism; Outcome; Participant; Pathogenesis; Pattern; Peripheral Blood Mononuclear Cell; Permeability; Pharmaceutical Preparations; Phase; Phenotype; Physicians; Pilot Projects; Placebo Control; Population; Pouchitis; Prevention; Probiotics; Production; Property; Randomized Clinical Trials; Regulatory T-Lymphocyte; Research; Research Personnel; Research Project Grants; Safety; Schools; Serum; Severities; Staging; Symptoms; T-Lymphocyte Subsets; Testing; Time; United States; Urine; Vulnerable Populations; Wheezing; Work; allergic response; base; cell mediated immune response; clinical efficacy; cohort; cytokine; expectation; experience; gastrointestinal; immunoregulation; improved; interest; lactic acid bacteria; microbial; novel; open label; particle; phase 2 study; placebo controlled study; prevent; pulmonary function; response; safety study; skin disorder; therapy duration; traditional therapy; zonulin

DESCRIPTION (provided by applicant): Alterations in gastrointestinal microbiota related to diet and common use of antibiotics are strongly associated with allergies and asthma. Probiotics (those microbes that produce only beneficial effects in the host gut), such as Lactobacillus and Bifidobacterium are reduced in the intestinal microbiota of atopic individuals and westernized populations. These probiotics have shown beneficial effects in the prevention and treatment of atopic disease, through improved intestinal barrier function and immunomodulation. One disease particularly in need of effective alternative therapy is asthma, which, along with other atopic diseases, is on the rise in the United States. Asthma results from deficient Treg responses leading to inappropriate TH2 cell-mediated immune response to common allergens, and several investigators have suggested that alteration of GI mucosal barrier function may be relevant to asthma pathogenesis. Traditional therapies focused on topical delivery to the lung to control inflammation have been insufficient perhaps because the intestinal mucosal barrier is dysfunctional. One multiorganism probiotic, VSL#3 contains 8 lactic acid bacteria, including Bifidobacterium and Lactobacillus species, which have synergistic properties for establishing stability of immunotolerant microbiota in chronic gastrointestinal disorders, restoring the gut barrier, and enhancing T cell regulatory function. Establishing a more favorable microbial balance in asthmatics could lead to a new strategy that will help control this and other chronic diseases affected by impaired GI mucosal function. Because the use of VSL#3 in asthma is novel, the FDA requires that we conduct an open label safety study of VSL#3 in this potentially vulnerable population before a placebo controlled trial; in the course of this Phase I safety study, mechanistic data regarding the health effects of VSL#3 can be acquired. Our overall goal is to restore mucosal barrier integrity in chronic diseases, with the expectation that this will lead to diminished clinical severity. The objective of this study is to evaluate the safety and efficacy of probiotic therapies in this regard, focusing on asthmatics, who have increased intestinal permeability and a TH2 allergic response to inhaled and ingested particles. HYPOTHESIS: The multiorganism probiotic, VSL#3, is safe and effective in asthmatics by improving intestinal barrier function and diverting the immune system to a more regulatory or tolerant state. Aim 1: To establish safety and potential efficacy of the commercially available probiotic, VSL#3, in asthmatics. Measurable safety outcomes before during and after twice daily consumption of VSL#3 for 3 months will include frequency of unscheduled asthma-related health care visits; number of days with asthma symptoms; frequency of asthma related work/school days missed; use of asthma rescue medications; and pulmonary function. We hypothesize that VSL#3 will be well tolerated. Aim 2: To test the ability of VSL#3 to enhance intestinal barrier function in asthmatics. We will measure intestinal permeability in this cohort to identify potential mechanisms to explain safety concerns and/or potential clinical benefit to subjects whose asthma control is measured in Aim 1 of this safety trial. We hypothesize that VSL#3 will be established in the GI tract, and will lead to improved intestinal barrier function in asthmatics in this safety trial. We will confirm that VSL#3 is viable in the GI tract of study participants to confirm adherence to therapy. Viability of the organism will be detected by stool collection and VSL#3 species identified by culture and real time PCR. Aim 3: To determine that VSL#3 in asthmatic subjects leads to immune tolerance. We will gather data on immune cell subsets using FACS analysis and spontaneous and activated peripheral blood mononuclear cell (PBMC) cytokine profiles of this cohort to identify potential mechanisms to explain safety concerns and/or potential clinical benefit to subjects whose asthma control is measured in Aim 1. Based on studies in other cohorts consuming VSL#3, we expect that VSL#3 will divert the immune system to a regulatory or tolerant mode with increased IL-10 production and downregulation of TH-2 cytokines IL- 4, IL-5, and IL-13.

描述（由申请人提供）：与饮食和常见抗生素有关的胃肠道菌群的改变与过敏和哮喘密切相关。益生菌（在宿主肠道中仅产生有益作用的微生物），例如乳酸杆菌和双歧杆菌，在特应性个体的肠道菌群和西方化的肠道中会降低。这些益生菌通过改善肠道屏障功能和免疫调节表现出对特应性疾病的预防和治疗的有益作用。一种特别需要有效替代疗法的疾病是哮喘，与其他特应性疾病一起在美国正在上升。哮喘是由于TREG反应不足导致TH2细胞介导的对常见过敏原的免疫反应的不适当，并且一些研究者表明，GI粘膜屏障功能的改变可能与哮喘发病机理有关。传统的疗法集中于局部向肺部进行控制以控制炎症，这可能是不够的，这可能是因为肠粘膜屏障功能失调。一种多生物益生菌VSL＃3包含8种乳酸细菌，包括双歧杆菌和乳酸杆菌，它们具有在慢性胃肠道疾病中建立免疫非耐脂质体的稳定性的协同特性，可恢复肠系膜屏障，并恢复T细胞调节型T细胞调节功能。在哮喘患者中建立更有利的微生物平衡可能会导致一种新的策略，该策略将有助于控制受胃肠道粘膜功能受损的慢性疾病。由于在哮喘中使用VSL＃3是新颖的，因此FDA要求我们在安慰剂对照试验之前对这一潜在脆弱人群进行开放标签安全研究。在本I阶段安全研究的过程中，可以获取有关VSL＃3的健康影响的机械数据。 我们的总体目标是恢复慢性疾病中的粘膜屏障完整性，并期望这会导致临床严重程度降低。这项研究的目的是评估这方面的益生菌疗法的安全性和功效，重点是哮喘，他们对吸入和摄入的颗粒的肠道通透性增加以及Th2过敏反应。假设：多生物生物，VSL＃3，通过改善肠道屏障功能并将免疫系统转移到更调节或耐受性状态，可以安全有效地哮喘。目标1：在哮喘患者中建立可获得的益生菌VSL＃3的安全性和潜在功效。在每天两次消耗3个月的VSL＃3之前和之后，可测量的安全结果将包括未定义的与哮喘相关的医疗访问的频率；哮喘症状的天数；错过了哮喘相关工作/上学日的频率；使用哮喘救援药物；和肺功能。我们假设VSL＃3将得到很好的耐受性。目标2：测试VSL＃3的能力增强哮喘患者肠道屏障功能。我们将在该队列中衡量肠道渗透性，以确定潜在的机制，以解释安全问题和/或潜在的临床益处，以在此安全试验的AIM 1中测量哮喘控制的受试者。我们假设VSL＃3将在胃肠道中建立，并将在这项安全试验中导致哮喘患者的肠道屏障功能改善。我们将确认VSL＃3在研究参与者的GI范围内可行，以确认遵守治疗。粪便收集和VSL＃3物种将通过培养和实时PCR识别。目标3：确定哮喘受试者中的VSL＃3会导致免疫耐受性。我们将使用FACS分析以及自发性和激活的周围血液单核细胞（PBMC）细胞因子特征的数据收集有关免疫细胞子集的数据或耐受模式，IL-10产生和Th-2细胞因子IL-4，IL-5和IL-13的产生和下调。