Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.
Department of Physiology, University of Tübingen, Tübingen, Germany.
Front Immunol. 2019 Jul 31;10:1737. doi: 10.3389/fimmu.2019.01737. eCollection 2019.
The gut microbiota influences several biological functions including immune responses. Inflammatory bowel disease is favorably influenced by consumption of several dietary natural plant products such as pomegranate, walnuts, and berries containing polyphenolic compounds such as ellagitannins and ellagic acid. The gut microbiota metabolizes ellagic acid resulting in the formation of bioactive urolithins A, B, C, and D. Urolithin A (UA) is the most active and effective gut metabolite and acts as a potent anti-inflammatory and anti-oxidant agent. However, whether gut metabolite UA affects the function of immune cells remains incompletely understood. T cell proliferation is stimulated by store operated Ca entry (SOCE) resulting from stimulation of Orai1 by STIM1/STIM2. We show here that treatment of murine CD4 T cells with UA (10 μM, 3 days) significantly blunted SOCE in CD4 T cells, an effect paralleled by significant downregulation of Orai1 and STIM1/2 transcript levels and protein abundance. UA treatment further increased miR-10a-5p abundance in CD4 T cells in a dose dependent fashion. Overexpression of miR-10a-5p significantly decreased STIM1/2 and Orai1 mRNA and protein levels as well as SOCE in CD4 T cells. UA further decreased CD4 T cell proliferation. Thus, the gut bacterial metabolite UA increases miR-10a-5p levels thereby downregulating Orai1/STIM1/STIM2 expression, store operated Ca entry, and proliferation of murine CD4 T cells.
肠道微生物群影响多种生物学功能，包括免疫反应。石榴、核桃和浆果等几种富含多酚化合物（如鞣花单宁和鞣花酸）的天然植物产品的消费对炎症性肠病有有利影响。肠道微生物群代谢鞣花酸，导致生物活性尿石素 A、B、C 和 D 的形成。尿石素 A（UA）是最活跃和有效的肠道代谢物，作为一种有效的抗炎和抗氧化剂。然而，肠道代谢物 UA 是否影响免疫细胞的功能仍不完全清楚。储存操作钙进入（SOCE）由 Orai1 被 STIM1/STIM2 刺激引起，刺激 T 细胞增殖。我们在这里表明，用 UA（10 μM，3 天）处理小鼠 CD4 T 细胞显著减弱了 CD4 T 细胞中的 SOCE，这种作用与 Orai1 和 STIM1/2 转录水平和蛋白丰度的显著下调平行。UA 处理进一步以剂量依赖的方式增加了 CD4 T 细胞中的 miR-10a-5p 丰度。miR-10a-5p 的过表达显著降低了 CD4 T 细胞中的 STIM1/2 和 Orai1 mRNA 和蛋白水平以及 SOCE。UA 进一步降低了 CD4 T 细胞的增殖。因此，肠道细菌代谢物 UA 增加了 miR-10a-5p 水平，从而下调了 Orai1/STIM1/STIM2 的表达、储存操作钙进入和小鼠 CD4 T 细胞的增殖。
