Mechanistic role of probiotic Lactobacillus reuteri in autoimmune lupus

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 系统性红斑狼疮患者肠道微生物区系的变化，包括乳杆菌属的显著减少 老鼠。我们的初步结果表明，增加乳杆菌属。在肠子里是有益的 减轻小鼠系统性红斑狼疮样疾病。这项提议的目标是机械地定义一个 益生菌，鲁氏乳杆菌(LR)，可预防系统性红斑狼疮。基于广泛的初步调查 观察到，我们假设LR通过加强肠道粘膜屏障和 调节Th17-Treg反应。在拟议的研究中，我们计划实现两个具体目标来测试这一点 假设。目的1重点研究乳杆菌对细菌的影响。对狼疮小鼠肠道微环境的影响。 这一目标的假设是益生菌通过调节肠道粘膜屏障来增强肠道粘膜屏障 紧密连接蛋白的表达。目标2侧重于系统层面的机制，通过 乳杆菌属减轻系统性红斑狼疮。这一目标的假设是，益生菌可以减弱类SLE 通过增加全身TGFb和诱导肾脏Treg细胞而致病。建议的研究结果如下： 转化为人类疾病，将确定启动导致人类系统性红斑狼疮的级联反应的关键事件，以及 使开发新的治疗目标成为必要，以产生治疗该疾病的方法。饮食和 已知可以改变肠道微生物区系的益生菌/益生菌有可能变得具有成本效益 系统性红斑狼疮管理战略的组成部分。

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.