VSL for Asthma

VSL 治疗哮喘

• 批准号: 7388385
• 负责人: Alessio Fasano
• 金额: $ 26.13万
• 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 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7388385
• 关键词: 17 year old; Address; Adherence; Adult; Affect; Age; Allergens; Allergic; Alternative Therapies; American; Antibiotics; Antigens; Appendix; 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; Daily; Data; Development; Diagnosis; Diet; Disease; Dose; Down-Regulation; Dyspnea; End Point; 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; Label; Lactobacillus; Lactulose; Lead; Lung; Mannitol; Measurable; Measures; Medical; Microbe; National Center for Complementary and Alternative Medicine; Numbers; Organism; Outcome; Participant; Pathogenesis; Pattern; Peripheral Blood Mononuclear Cell; Permeability; Personal Satisfaction; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phenotype; Physicians; Pilot Projects; Placebo Control; Polymerase Chain Reaction; Population; Pouchitis; Prevention; Probiotics; Production; Property; Purpose; Randomized Clinical Trials; Research; Research Personnel; Research Project Grants; Safety; Schools; Serum; Severities; Staging; Symptoms; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; United States; United States Food and Drug Administration; Urine; Vulnerable Populations; Wheezing; Work; base; cell mediated immune response; clinical efficacy; cohort; cytokine; day; expectation; experience; gastrointestinal; immunoregulation; improved; interest; lactic acid bacteria; microbial; novel; particle; placebo controlled study; prevent; pulmonary function; response; skin disorder; therapy duration; 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）：与饮食和抗生素常用有关的胃肠道微生物群的改变与过敏和哮喘密切相关。特应性个体和西方人群肠道微生物群中的益生菌（仅在宿主肠道中产生有益作用的微生物），例如乳酸菌和双歧杆菌，数量减少。这些益生菌通过改善肠道屏障功能和免疫调节，在预防和治疗特应性疾病方面显示出有益的作用。哮喘是一种特别需要有效替代疗法的疾病，它与其他特应性疾病一起在美国呈上升趋势。哮喘是由 Treg 反应缺陷导致 TH2 细胞介导的对常见过敏原的不适当的免疫反应引起的，一些研究人员表明胃肠道粘膜屏障功能的改变可能与哮喘发病机制有关。传统疗法侧重于局部递送至肺部以控制炎症，但这种疗法并不充分，这可能是因为肠粘膜屏障功能失调。 VSL#3 是一种多生物益生菌，含有 8 种乳酸菌，包括双歧杆菌和乳杆菌，它们具有协同特性，可在慢性胃肠道疾病中建立免疫耐受微生物群的稳定性，恢复肠道屏障，并增强 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带来一种新的策略，有助于控制哮喘病和其他受胃肠道粘膜功能受损影响的慢性疾病。由于 VSL#3 在哮喘中的应用是新颖的，FDA 要求我们在安慰剂对照试验之前对这一潜在易感人群进行 VSL#3 的开放标签安全性研究；在第一阶段安全性研究的过程中，可以获得有关 VSL#3 对健康影响的机械数据。 我们的总体目标是恢复慢性疾病粘膜屏障的完整性，期望这将导致临床严重程度减轻。本研究的目的是评估益生菌疗法在这方面的安全性和有效性，重点关注哮喘患者，因为哮喘患者的肠道通透性增加，并对吸入和摄入的颗粒产生 TH2 过敏反应。假设：多生物益生菌 VSL#3 通过改善肠道屏障功能并将免疫系统转移到更具调节性或耐受性的状态，对哮喘患者安全有效。目标 1：确定市售益生菌 VSL#3 对哮喘患者的安全性和潜在功效。连续 3 个月每天两次服用 VSL#3 之前和之后的可测量安全结果将包括计划外的哮喘相关医疗保健就诊的频率；出现哮喘症状的天数；缺勤与哮喘相关的工作/上课的频率；使用哮喘急救药物；和肺功能。我们假设 VSL#3 具有良好的耐受性。目标 2：测试 VSL#3 增强哮喘患者肠道屏障功能的能力。我们将测量该队列中的肠道通透性，以确定潜在的机制来解释安全性问题和/或对该安全性试验的目标 1 中测量哮喘控制的受试者的潜在临床益处。我们假设 VSL#3 将在胃肠道中建立，并在本次安全试验中改善哮喘患者的肠道屏障功能。我们将确认 VSL#3 在研究参与者的胃肠道中是可行的，以确认治疗的依从性。将通过粪便采集检测微生物的活力，并通过培养和实时 PCR 鉴定 VSL#3 物种。目标 3：确定哮喘受试者中的 VSL#3 会导致免疫耐受。我们将使用 FACS 分析以及该队列的自发和激活的外周血单核细胞 (PBMC) 细胞因子谱来收集有关免疫细胞亚群的数据，以确定潜在的机制，以解释安全性问题和/或对在 Aim 中测量哮喘控制的受试者的潜在临床益处1. 根据其他服用 VSL#3 队列的研究，我们预计 VSL#3 会将免疫系统转移到调节或耐受模式，增加 IL-10 的产生并下调 TH-2 细胞因子 IL-4、 IL-5 和 IL-13。