Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
Department of Laboratory Animal Science, College of Basic Medical Sciences, Third Military Medical University, Chongqing, 400038, China.
Cell Res. 2019 Jul;29(7):516-532. doi: 10.1038/s41422-019-0190-3. Epub 2019 Jun 14.
Long-range communication between intestinal symbiotic bacteria and extra-intestinal organs can occur through circulating bacterial signal molecules, through neural circuits, or through cytokines or hormones from host cells. Here we report that Nod1 ligands derived from intestinal bacteria act as signal molecules and directly modulate insulin trafficking in pancreatic beta cells. The cytosolic peptidoglycan receptor Nod1 and its downstream adapter Rip2 are required for insulin trafficking in beta cells in a cell-autonomous manner. Mechanistically, upon recognizing cognate ligands, Nod1 and Rip2 localize to insulin vesicles, recruiting Rab1a to direct insulin trafficking through the cytoplasm. Importantly, intestinal lysozyme liberates Nod1 ligands into the circulation, thus enabling long-range communication between intestinal microbes and islets. The intestine-islet crosstalk bridged by Nod1 ligands modulates host glucose tolerance. Our study defines a new type of inter-organ communication based on circulating bacterial signal molecules, which has broad implications for understanding the mutualistic relationship between microbes and host.
肠道共生菌与肠外器官之间的长程通讯可以通过循环细菌信号分子、神经回路、宿主细胞的细胞因子或激素进行。在这里，我们报告肠道细菌衍生的 Nod1 配体可作为信号分子，并直接调节胰腺β细胞中的胰岛素转运。胞质肽聚糖受体 Nod1 及其下游衔接蛋白 Rip2 以细胞自主的方式在β细胞中参与胰岛素转运。在机制上，Nod1 和 Rip2 在识别同源配体后定位于胰岛素囊泡，募集 Rab1a 以通过细胞质指导胰岛素转运。重要的是，肠道溶菌酶将 Nod1 配体释放到循环中，从而使肠道微生物和胰岛之间能够进行长程通讯。由 Nod1 配体桥接的肠-胰岛串扰调节宿主葡萄糖耐量。我们的研究定义了一种基于循环细菌信号分子的新型器官间通讯，这对理解微生物与宿主之间的共生关系具有广泛的意义。
