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: 10004045
• 负责人: Graciela L Lorca
• 金额: $ 57.85万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10004045
• 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; Epithelium; 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)，微生物群失调被认为是免疫耐受和启动中断的诱发因素 β细胞自身免疫。益生菌微生物可用于预防或恢复这种菌群失调。我们 此前曾在啮齿动物中使用约氏乳杆菌 N6.2 进行过干预研究，发现 施用微生物可降低 T1D 的发病率。将我们的啮齿动物研究转化为 人类预防 T1D 的潜在方法需要在健康个体中进行初步研究。我们 对 42 名没有已知 T1D 危险因素的健康个体进行了一项双盲、随机临床试验 评估受试者对食用约氏乳杆菌 N6.2 的反应。约氏乳杆菌N6.2的施用是 在成人对照受试者中具有良好的耐受性，显示出对先天性和适应性免疫的系统性影响 种群并导致犬尿氨酸/色氨酸比率下降。这些数据为 在 T1D 风险受试者的预防试验中使用约氏乳杆菌 N6.2 的安全性和可行性。长期来看 我们研究的目标是确定服用约氏乳杆菌或其成分可以预防 T1D 儿童发病。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 成人 T1D 患者的耐受性。作为该提案的次要结果，我们假设政府 约氏乳杆菌 N6.2 将在 T1D 和 T1D 背景下促进宿主免疫系统的耐受性偏差 可能保留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 约氏乳杆菌 N6.2 在 T1D 成人中的作用，确定约氏乳杆菌 N6.2 在 T1D 患者免疫细胞激活中的作用 患有 T1D 的成人并阐明细菌介导的系统信号转导机制 效应器组件。完成此提案后，我们将确定 L 的消耗量。 约氏菌 N6.2 对于患有 T1D 的成人来说是安全的，对疾病进展没有不利影响。我们进一步期望 已经收集了关于宿主全身反应的细菌效应子的证据。中获得的数据 该提案将为使用约氏乳杆菌 N6.2 在有风险的受试者中进行预防试验提供垫脚石 T1D。