Investigating immumomodulatory mechanisms of probiotics

共生微生物以共生的方式生活在宿主体内。益生菌是活的共生菌，几个世纪以来一直用于补充正常或有益的肠道和泌尿生殖微生物群。我的长期研究目标是了解宿主如何维持与共生菌的免疫共生关系，以及益生菌对宿主的免疫作用。在过去5年的NSERC支持下，我们的研究项目主要集中在揭示宿主细胞感知细菌益生菌的机制及其对宿主免疫反应的影响。我们证实了鼠李糖乳杆菌GR1及其分泌产物对巨噬细胞、树突状细胞、肠固有层细胞和胎盘滋养细胞具有免疫调节作用。GR1以及鼠李糖乳杆菌其他菌株在这些细胞中优先和有效地产生免疫调节细胞因子粒细胞集落刺激因子（G-CSF），该因子可能在维持肠道和胎盘的免疫稳态中发挥重要作用。本课题拟进一步研究GR1、GR1分泌因子和G-CSF调节巨噬细胞分化、活化和存活的细胞及信号机制。本研究的具体目的如下：目的1：鉴定/纯化gr1因子，并研究巨噬细胞中优先产生G-CSF的gr1因子的信号传导和表观遗传机制。目标2。探讨G-CSF在骨髓细胞、THP-1细胞和肠道巨噬细胞分化和存活中的作用和机制。拟议的研究将提供有关乳酸菌如何调节巨噬细胞活化以及暴露于乳酸菌的巨噬细胞大量产生的G-CSF如何影响骨髓细胞分化和细胞存活的详细信息。总的来说，这些研究将揭示共生菌和益生菌如何调节宿主免疫系统并维持宿主的共生关系。

Commensal microbes live inside the host in symbiosis. Probiotics are live commensals that have been used for centuries to replenish normal or beneficial gut and urogenital microflora. Long-term objectives of my research program are to understand how the host maintains immunological symbiosis with commensals and what immunological effects probiotics have on the host. During the last 5 years of NSERC support, our research program has focused on unraveling the mechanisms of the host cells in sensing bacterial probiotics and their effects on the host immune responses. We have demonstrated that the probiotic strain of Lactobacillus rhamnosus GR1 (GR1) and its secreted products have immunomodulatory effects on macrophages, dendritic cells, intestinal lamina propria cells and placental trophoblasts. GR1 as well as other strains of Lactobacillus rhamnosus preferentially and potently produce the immunomodulatory cytokine granulocyte colony-stimulating factor (G-CSF) in these cells, which may play important roles in maintaining immunological homeostasis of intestine and placenta. This research proposal is to further study the cellular and signaling mechanisms by which GR1, GR1-secreted factor(s) and G-CSF in modulating macrophage differentiation, activation and survival. The followings are specific aims of the study:Aim 1: Identify/purify the GR1-factor(s), and examine its/their signaling and epigenetic mechanisms responsible for preferential production of G-CSF in macrophages. Aim 2. Examining the role and mechanisms of G-CSF in macrophage differentiation and survival in bone marrow cells, THP-1 cells and the intestine. The proposed study will provide detailed information on how lactobacilli modulate macrophage activation and how G-CSF highly produced by lactobacillus-exposed macrophages affects myeloid cell differentiation and cell survival. Overall, these studies will unravel how commensals and probiotics modulate the host immune system and maintain symbiosis in the host.