Investigating immumomodulatory mechanisms of probiotics

共生微生物在宿主体内共生。益生菌是几个世纪以来一直被用来补充正常或有益的肠道和泌尿生殖系统微生物的活的共生体。我的研究计划的长期目标是了解宿主如何维持与共生的免疫共生，以及益生菌对宿主的免疫影响。在过去5年的NSERC支持期间，我们的研究计划集中在揭开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。我们已经证明，鼠李糖乳杆菌GR1及其分泌产物对巨噬细胞、树突状细胞、肠道固有层细胞和胎盘滋养层细胞具有免疫调节作用。GR1和其他鼠李糖乳杆菌一样，优先和有效地在这些细胞中产生免疫调节细胞因子粒细胞集落刺激因子(G-CSF)，这可能在维持肠道和胎盘的免疫动态平衡中发挥重要作用。本研究拟进一步研究GR1、GR1分泌因子(S)和G-CSF在调节巨噬细胞分化、激活和存活中的细胞和信号机制。本研究的具体目的如下：目的1：鉴定和纯化GR1因子(S)，并研究其在巨噬细胞优先产生G-CSF的信号和表观遗传学机制。目的2.探讨粒细胞集落刺激因子在骨髓细胞、THP-1细胞和肠道巨噬细胞分化和存活中的作用及其机制。这项拟议的研究将提供有关乳杆菌如何调节巨噬细胞激活以及暴露于乳杆菌的巨噬细胞高水平产生G-CSF如何影响髓系细胞分化和细胞存活的详细信息。总体而言，这些研究将揭开共生菌和益生菌如何调节宿主免疫系统并维持宿主中的共生。

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.