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相关的胃肠道微生物群变化与过敏和哮喘密切相关。益生菌（那些只在宿主肠道中产生有益作用的微生物），如乳酸杆菌和双歧杆菌，在特应性个体和西化人群的肠道微生物群中减少。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效果。一种特别需要有效替代疗法的疾病是哮喘，它与其他特应性疾病一起沿着在美国呈上升趋势。哮喘是由于Treg应答缺陷导致对常见过敏原的不适当的TH 2细胞介导的免疫应答，并且一些研究者已经提出GI粘膜屏障功能的改变可能与哮喘发病机制相关。集中于局部递送至肺部以控制炎症的传统疗法已经不足，这可能是因为肠粘膜屏障功能障碍。一种多生物体益生菌，VSL#3含有8种乳酸菌，包括双歧杆菌属和乳杆菌属，其具有协同特性，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导致一种新的策略，这将有助于控制这种疾病和其他受胃肠道粘膜功能受损影响的慢性疾病。由于VSLI #3在哮喘中的使用是新的，FDA要求我们在安慰剂对照试验之前在该潜在易感人群中进行VSLI #3的开放标签安全性研究;在该I期安全性研究过程中，可以获得关于VSLI #3健康效应的机制数据。 我们的总体目标是恢复慢性疾病的粘膜屏障完整性，并期望这将导致临床严重程度降低。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，重点是哮喘患者，他们的肠道通透性增加，对吸入和摄入的颗粒有TH 2过敏反应。假设：多生物体益生菌VSLI #3通过改善肠道屏障功能和将免疫系统转移到更受调节或耐受的状态，对哮喘患者安全有效。目的1：确定市售益生菌VSLI #3在哮喘患者中的安全性和潜在疗效。VSLI #3每日两次给药前、给药期间和给药后3个月的可测量安全性结局包括计划外哮喘相关医疗保健访视频率;出现哮喘症状的天数;哮喘相关工作/上学日缺课频率;哮喘急救药物的使用;和肺功能。我们假设VSLI #3的耐受性良好。目的2：检测VSLI #3增强哮喘患者肠屏障功能的能力。我们将测量该队列的肠道通透性，以确定潜在机制，解释安全性问题和/或对哮喘控制在本安全性试验目的1中测量的受试者的潜在临床获益。我们假设VSLI #3将在胃肠道中确立，并将在本安全性试验中改善哮喘患者的肠屏障功能。我们将确认VSLI #3在研究受试者的胃肠道中具有活性，以确认治疗依从性。将通过粪便采集检测微生物的活力，并通过培养和真实的PCR鉴别VSLI #3菌种。目的3：确定哮喘受试者中VSLI #3导致免疫耐受。我们将使用FACS分析收集该队列的免疫细胞亚群数据以及自发和活化的外周血单核细胞（PBMC）细胞因子谱，以确定解释安全性问题的潜在机制和/或在目标1中测量哮喘控制的受试者的潜在临床获益。基于在服用VSLI #3的其他队列中的研究，我们预期VSLI #3将使免疫系统转向调节或耐受模式，IL-10产生增加，TH-2细胞因子IL- 4、IL-5和IL-13下调。