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)：与饮食和抗生素的常用有关的胃肠道微生物区系的改变与过敏和哮喘密切相关。益生菌(那些只在宿主肠道产生有益影响的微生物)，如乳杆菌和双歧杆菌，在特应性个体和西方化人群的肠道微生物区系中减少。这些益生菌通过改善肠道屏障功能和免疫调节，在特应性疾病的预防和治疗中显示出良好的效果。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样，在美国呈上升趋势。哮喘是由于Treg反应缺陷导致TH2细胞对常见变应原的免疫应答异常所致，一些研究人员认为GI粘膜屏障功能的改变可能与哮喘的发病有关。传统的治疗方法主要集中在肺部局部给药以控制炎症，这可能是因为肠道粘膜屏障功能失调。一种多菌益生菌VSL#3含有双歧杆菌和乳杆菌等8种乳酸菌，它们在建立慢性胃肠道疾病免疫耐受微生物区系的稳定性、恢复肠道屏障和增强T细胞调节功能方面具有协同作用。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，这将有助于控制这一疾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在哮喘中的使用是新的，FDA要求我们在进行安慰剂对照试验之前，在这一潜在的脆弱人群中进行VSL#3的开放标签安全性研究；在这项I期安全性研究的过程中，可以获得关于VSL#3对健康影响的机械学数据。 我们的总体目标是恢复慢性疾病的粘膜屏障完整性，期望这将导致临床严重程度的减轻。这项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，重点是哮喘患者，他们对吸入和摄入的颗粒物有更高的肠道通透性和TH2过敏反应。假设：多菌益生菌VSL#3对哮喘患者安全有效，它可以改善肠道屏障功能，并将免疫系统转移到更具调节性或耐受性的状态。目的1：确定市售益生菌VSL#3对哮喘患者的安全性和潜在疗效。在连续3个月每天服用两次VSL#3之前、期间和之后，可衡量的安全结果将包括与哮喘相关的非计划医疗就诊频率、出现哮喘症状的天数、与哮喘相关的工作/上学天数、哮喘救援药物的使用以及肺功能。我们假设VSL#3将被很好地容忍。目的：检测VSL#3对哮喘患者肠屏障功能的增强作用。我们将在这个队列中测量肠道通透性，以确定解释安全问题和/或对哮喘控制的潜在临床益处的潜在机制，这些受试者的哮喘控制是在这项安全试验的目标1中衡量的。在这项安全性试验中，我们假设VSL#3将在胃肠道内建立，并将导致哮喘患者肠道屏障功能的改善。我们将确认VSL#3在研究参与者的胃肠道中是可行的，以确认坚持治疗。微生物的生存能力将通过粪便收集和VSL#3菌种的培养和实时荧光PCR鉴定来检测。目的：确定哮喘患者VSL#3导致免疫耐受。我们将使用FACS分析收集免疫细胞亚群的数据，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，以确定潜在的机制，以解释安全问题和/或潜在的临床益处，这些受试者的哮喘控制是在AIM 1中进行的。基于对其他服用VSL#3的队列的研究，我们预计VSL#3将通过增加IL-10的产生和下调TH-2细胞因子IL-4、IL-5和IL-13的表达，将免疫系统转移到调节或耐受模式。