Mechanistic role of probiotic Lactobacillus reuteri in autoimmune lupus

益生菌罗伊氏乳杆菌在自身免疫性狼疮中的机制作用

• 批准号: 10089144
• 负责人: Xin M Luo
• 金额: $ 32.69万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-05 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10089144
• 关键词: Affect; Antibodies; Attenuated; Autoantibodies; Autoimmune; Autoimmune Diseases; Autoimmunity; Bacteria; Biological Assay; Blood Circulation; Cells; Complex; Dependence; Deposition; Development; Diet; Disease; Drug Side Effects; Endotoxins; Epithelial; Equilibrium; Event; Genes; Genetic Transcription; Goals; Gut Mucosa; Human; Immunosuppressive Agents; In Vitro; Inbred MRL lpr Mice; Interleukin-6; Intestinal permeability; Kidney; Knowledge; Lactobacillus; Lactobacillus reuteri; Lipopolysaccharides; Lupus; Mediating; Mus; Oral; Pathogenesis; Pathway interactions; Patients; Phenotype; Probiotics; Proteins; Proteinuria; RNA; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Role; Serum; Spleen; Systemic Lupus Erythematosus; T cell differentiation; Testing; Tight Junctions; Up-Regulation; base; cost effective; fecal microbiota; fluorescein isothiocyanate dextran; gastrointestinal epithelium; gut colonization; gut dysbiosis; gut microbiota; human disease; intestinal barrier; intestinal epithelium; intraperitoneal; mouse model; neutralizing antibody; new therapeutic target; novel therapeutics; prebiotics; prevent; promoter; response; standard of care; systemic autoimmunity; transcription factor; transcriptome sequencing; translation to humans; treatment strategy; zonulin

Project Summary Systemic lupus erythematosus (SLE) is a complex autoimmune disease with no known cure. We observed changes of gut microbiota in SLE, including a marked decrease of Lactobacillus spp., in both human and mouse. Our preliminary results showed that increasing Lactobacillus spp. in the gut is beneficial and attenuates SLE-like disease in mice. The goal of this proposal is to mechanistically define the role of a probiotic species, Lactobacillus reuteri (LR), that protects against SLE. Based on extensive preliminary observations, we hypothesize that LR attenuates lupus by strengthening the gut mucosal barrier and modulating the Th17-Treg response. In the proposed studies, we plan to achieve two specific aims to test this hypothesis. Aim 1 is focused on the impact of Lactobacillus spp. on the gut microenvironment in lupus mice. The hypothesis of this aim is that the probiotic bacteria strengthen the gut mucosal barrier by modulating the expression of tight junction proteins. Aim 2 is focused on the mechanism at the systemic level by which Lactobacillus spp. attenuate SLE. The hypothesis of this aim is that the probiotic bacteria attenuates SLE-like disease by increasing systemic TGFb and inducing renal Treg cells. The results of the proposed studies, upon translation to human disease, will identify the key events initiating the cascade that leads to human SLE, and enable development of new therapeutic targets necessary to generate treatments for the disease. Diet and probiotics/prebiotics, known to modify the gut microbiota, have the potential to become cost-effective components of SLE management strategies.

项目摘要 系统性红斑狼疮（SLE）是一种复杂的自身免疫性疾病，目前尚无治愈方法。我们观察到 SLE患者肠道菌群的变化，包括乳酸杆菌的显著减少，在人力和 老鼠.我们的初步研究结果表明，增加乳酸杆菌。在肠道中是有益的， 减弱小鼠中的SLE样疾病。本提案的目标是机械地界定 益生菌，罗伊氏乳杆菌（LR），防止SLE。根据广泛的初步 根据观察，我们假设LR通过加强肠粘膜屏障来减弱狼疮， 调节Th 17-Treg应答。在拟议的研究中，我们计划达到两个具体目标，以测试这一点 假说.目的1集中于乳酸杆菌属的影响。对狼疮鼠肠道微环境的影响 该目的的假设是益生菌通过调节肠粘膜屏障来增强肠粘膜屏障。 紧密连接蛋白的表达。目标2侧重于系统一级的机制， 乳杆菌属减轻系统性红斑狼疮。这一目标的假设是，益生菌减弱SLE样 通过增加全身性TGFb和诱导肾Treg细胞来治疗疾病。建议研究的结果， 翻译为人类疾病，将确定启动导致人类SLE级联反应的关键事件， 能够开发产生疾病治疗所需的新治疗靶点。饮食和 益生菌/益生元，已知可以改变肠道微生物群，有可能变得具有成本效益 SLE管理策略的组成部分。