Evaluation of safety, tolerability and immunological responses to Lactobacillus johnsonii N6.2 supplementation in adults with Diabetes type 1

成人 1 型糖尿病患者补充约氏乳杆菌 N6.2 的安全性、耐受性和免疫反应评估

• 批准号: 10217121
• 负责人: Graciela L Lorca
• 金额: $ 65.66万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10217121
• 关键词: Adult; Adverse effects; Animals; Apoptosis; Autoimmunity; Bacteria; Beta Cell; Bifidobacterium; Biological Assay; Blood; Blood Circulation; C-Peptide; CD8-Positive T-Lymphocytes; Cell Line; Cell physiology; Cells; Child; Consumption; Culture-independent methods; Data; Development; Diabetes Mellitus; Diabetes prevention; Disease Progression; Distant; Double-Blind Method; Environment; Epithelial; Evaluation; Extracellular Structure; Frequencies; Genetic; Genetic Predisposition to Disease; Goals; Health; Health Status; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunophenotyping; Incidence; Individual; Insulin-Dependent Diabetes Mellitus; Intake; Intervention Studies; Intestines; Knowledge; Kynurenine; Lactobacillus; Location; Mediating; Mediator of activation protein; Methods; Natural Killer Cells; Pilot Projects; Population; Prevention; Prevention trial; Probiotics; Randomized Clinical Trials; Rattus; Research; Residual state; Resistance; Risk; Risk Factors; Rodent; Rodent Model; Role; Safety; Sampling; Serum; Signal Transduction; Site; Stream; Supplementation; T-Lymphocyte Subsets; Translating; Tryptophan; aged; associated symptom; base; beneficial microorganism; cell type; cytokine; dietary supplements; disorder prevention; dysbiosis; extracellular; gut microbiota; host-microbe interactions; illness length; immune activation; insulin dependent diabetes mellitus onset; intestinal epithelium; member; microbial; microbiota; microorganism; monocyte; nanovesicle; peripheral blood; preservation; prevent; reduce symptoms; response; safety and feasibility; safety testing; secondary outcome

While genetics has been demonstrated to represent a major risk factor for the development of type 1 diabetes (T1D), microbiota dysbiosis has been suggested as an elicitor of a break in immunological tolerance and initiation of β-cell autoimmunity. Probiotic microorganisms may be used to prevent or restore this dysbiosis. We have previously performed an intervention study using L. johnsonii N6.2 in rodents and found that the administration of the microorganism reduced the incidence of T1D. Translating our rodent studies towards a potential method for T1D prevention in humans required a pilot study in healthy individuals. We conducted a double-blind, randomized clinical trial in 42 healthy individuals with no known risk factors for T1D to evaluate subject responses to the consumption of L. johnsonii N6.2. The administration of L. johnsonii N6.2 was well tolerated in adult control subjects, demonstrated systemic impacts on innate and adaptive immune populations and resulted in a decreased kynurenine/tryptophan ratio. These data provide support for the safety and feasibility of using L. johnsonii N6.2 in prevention trials in subjects at risk for T1D. The long term goal of our research is to determine that the administration of L. johnsonii or its constituents will prevent T1D onset in children. As a step in that direction, the primary goal of this proposal is to test the safety and tolerability in adults with T1D. As a secondary outcome of this proposal, we hypothesize that the administration of L. johnsonii N6.2 will promote tolerogenic skewing of the host immune system in the context of T1D and may preserve β-cell function. We will achieve the goals of this proposal by evaluating the safety and tolerability of L. johnsonii N6.2 in adults with T1D, determining the role of L. johnsonii N6.2 in immune cell activation in adults with T1D and elucidating the mechanism of systemic signal transduction mediated by bacterial effector components. After completion of this proposal, we will have determined that the consumption of L. johnsonii N6.2 is safe for adults with T1D with no adverse effects on disease progression. We further expect to have gathered evidence on the bacterial effectors of systemic responses in the host. The data obtained in the proposal will provide a stepping stone for the use of L. johnsonii N6.2 in prevention trials in subjects at risk for T1D.

虽然遗传学已被证明是1型糖尿病发展的主要危险因素 （T1D），已提出微生物群的症状，以此作为免疫耐受性和起始中断的诱因 β细胞自身免疫。益生菌微生物可用于预防或恢复这种营养不良。我们 以前曾在啮齿动物中使用L. johnsonii N6.2进行了干预研究，发现 微生物的给药减少了T1D的事件。将我们的啮齿动物研究转化为 人类预防T1D的潜在方法需要对健康个体进行试点研究。我们 在42个健康个体中进行了双盲，随机临床试验，没有T1D的已知风险因素 评估主题对消费乳杆菌N6.2的反应。 L. johnsonii N6.2的管理是 在成人对照对象中耐受性良好，表现出对先天和适应性免疫的全身影响 种群，导致雌激素/色氨酸比率降低。这些数据为 使用L. johnsonii N6.2在有T1D风险的受试者的预防试验中的安全性和可行性。长期 我们研究的目标是确定约翰逊乳杆菌或其构成的管理将阻止T1D 儿童发作。作为朝这个方向迈出的一步，该提案的主要目标是测试安全性和 T1D成人的耐受性。作为该提议的次要结果，我们假设政府 约翰逊·诺（L. johnsonii N6.2 可以保留β细胞功能。我们将通过评估安全性和耐受性来实现该提案的目标 L. johnsonii N6.2在具有T1D的成年人中，确定了约翰逊氏乳杆菌N6.2在免疫细胞激活中的作用 具有T1D的成年人并阐明了细菌介导的全身信号转导机制 效应子组件。该提案完成后，我们将确定L.的消费。 Johnsonii N6.2对具有T1D的成年人安全，对疾病进展没有不利影响。我们进一步期望 已经收集了有关宿主全身反应的细菌影响的证据。在 提案将为使用L. johnsonii n6.2在有风险的受试者的预防试验中提供垫脚石 T1D。