肠道丁酸在1型糖尿病免疫炎症中作用及分子机制研究

Type 1 diabetes (T1D) is a devastating autoimmune disease characterized by autoimmune T cell directed islet destruction and insulin deprivation. Gut microbiota and dysregulated pancreatic immune environment are intrinsically associated with the disease pathogenesis. Butyric acid (BTA) is a gut commensal microbe metabolite. Recently, it has been demonstrated to exert regulatory effects on regulatory T cells (Treg) via its inhibitory activities on histone deacetylase or HDAC. BTA also induces expression of the host defense peptides CRAMP with immunomodulatory functions highlighted in various contexts. Our earlier data has importantly shown that butyrate levels are altered (decreased) in NOD female mice suggesting a defective BTA production in diabetic mice. In addition, BTA administered to prediabetic NOD female dampened the incidence of autoimmune diabetes and induced CRAMP production by islet cells. CRAMP administration induced regulatory immune cells and balanced the pro- and anti-inflammatory cytokines within the pancreatic micoenvironment. In the current project, we aim to further demonstrate the correlation of butyrate levels with clinical and experimental T1D, investigate regulatory effects of gut microbiota-derived BTA via CRAMP on various islet immune cells, the detailed molecular mechanisms including signaling pathways, key transcriptional factors/activators and targeted anti- vs. pro-inflammatory cytokines. This project will contribute to current understanding on pathogenesis of T1D in connection to gut microbiota and metabolites, unveil BTA and CRAMP as the critical molecules which directly regulate islet immune environment, and provide novel targets for intervening T1D.

肠道菌群环境和胰岛免疫炎症与1型糖尿病（T1D）发生有着密切关联。丁酸（BTA）是肠道共生菌代谢产物，最近研究表明BTA可通过抑制组蛋白去乙酰化酶（HDAC）活性调节调节性T细胞（Treg）的功能并可诱导免疫及非免疫来源的宿主防御肽CRAMP的表达。CRAMP具有显著的免疫调节功能。我们研究表明BTA可降低NOD雌鼠T1D发病率并上调胰岛内CRAMP水平，而给予NOD小鼠CRAMP可调控胰岛内调节性免疫细胞比例和抑炎/促炎细胞因子的平衡。本项目将结合T1D临床病人、自发性T1D小鼠、CRAMP基因敲除模式动物和体外培养胰岛免疫细胞模型，分析研究肠道来源的BTA通过诱导CRAMP在调节T1D过程中对胰岛免疫细胞（Treg、DC、巨噬细胞）表型、信号通路、炎症因子、肠道免疫稳态的作用及分子机制。本项目将揭示肠道BTA通过调控CRAMP关键分子直接影响胰岛免疫环境，为干预T1D提供新策略。

肠道菌群环境和胰岛免疫炎症与1型糖尿病（T1D）发生有着密切关联。丁酸（BTA）是肠道共生菌代谢产物，最近研究表明BTA可通过抑制组蛋白去乙酰化酶（HDAC）活性调节调节性T细胞（Treg）的功能并可诱导免疫及非免疫来源的宿主防御肽CRAMP的表达。CRAMP具有显著的免疫调节功能。我们研究表明BTA可降低NOD雌鼠T1D发病率并上调胰岛内CRAMP水平，而给予NOD小鼠CRAMP可调控胰岛内调节性免疫细胞比例和抑炎/促炎细胞因子的平衡。本项目研究表明CRAMP在胰岛β细胞中组成性表达；肠道BTA能够诱导IL-1β或LPS刺激的胰岛β细胞以及NOD小鼠表达CRAMP，CRAMP能够通过其受体EGFR调节p-Bad, Bcl-2, and Bcl-xL发挥防止β细胞损伤。而CRAMP-/-小鼠胰岛素分泌减少，给予外源性CRAMP能够改善T1D小鼠的血糖；而通过特异性膳食纤维或产丁酸菌可改善NOD小鼠肠道菌群上调肠道丁酸发挥上述作用；本项目将揭示肠道BTA通过调控CRAMP关键分子直接影响胰岛免疫环境，为干预T1D提供新策略