从清道夫受体A-枯否细胞调节途径探讨岩藻多糖改善IUGR仔猪肠-肝轴功能的机制

Intra-uterine growth retardation (IUGR) seriously impairs the growth performance and health status of piglets and it is a thorny issue faced by swine industry. Gut and liver injuries are the main factors contributing to growth lag and weakened disease resistance of IUGR piglets. However, the relevant mechanism is still unclear, and the effective interventions are relatively scarce. Combining with the understanding of physiopathology for the “gut-liver axis” system and the findings obtained from previous studies, we suppose that the abnormal changes in the number and polarization of Kupffer cells are the key events inducing the progressive amplification of inflammatory response and the vicious circle between gut and liver injuries in the IUGR piglets. Scavenger receptor A (SR-A) has the capacity to regulate the function of Kupffer cells and relevant inflammatory response. It may be a target for nutritional intervention. Therefore, this project will adopt the strategy of gain-and loss-of-function, investigating the regulatory role of SR-A on the Kupffer cells of IUGR piglets. Then, we will employ the method of combining experiments both in vivo and in vitro, to explore the effects of fucoidan on Kupffer cells, hepatic metabolism, intestinal barrier, and microflora from the molecular, cellular, and whole animal levels, integrating the underlying mechanism by which fucoidan protects the function of gut-liver axis of the IUGR weaned piglets, with the aid of the multi-omics conjoint analysis. The results will provide new targets and approaches for improving the gut and liver injuries and physical health of the IUGR piglets.

宫内发育迟缓（IUGR）严重影响仔猪生长发育和健康水平，是生猪养殖面临的一个棘手问题。肠、肝损伤是导致IUGR仔猪生长缓慢和抗病力弱的重要因素，但其机制仍未阐明，有效的干预手段也较为缺乏。结合生理病理学对“肠-肝轴”系统的认识与前期研究结果，我们认为枯否细胞数量和极性的异常变化是导致IUGR仔猪炎症反应逐级放大以及肠、肝损伤恶性循环的关键环节。清道夫受体A（SR-A）具有调节枯否细胞功能与炎症反应等作用，有望成为营养调控的干预靶点。因此，本研究将运用功能获得与缺失策略，明确SR-A对IUGR仔猪枯否细胞的调节作用。随后体内、外试验相结合，从分子、细胞和整体动物水平，解析SR-A天然配体——岩藻多糖对枯否细胞、肝脏代谢、肠道屏障及微生物区系的影响，借助多组学联合分析技术，整合岩藻多糖对IUGR断奶仔猪肠-肝轴功能的保护机制。预期成果可为改善IUGR仔猪肠、肝损伤与机体健康提供新靶点和新思路。

宫内发育迟缓（IUGR）严重影响仔猪生长发育和健康水平，是生猪养殖面临的一个棘手问题。肠、肝损伤是导致IUGR仔猪生长缓慢和抗病力弱的重要因素，但其机制仍未阐明，有效的干预手段也较为缺乏。结合生理病理学对“肠肝轴”系统的认识与前期研究结果，我们认为枯否细胞数量和极性的异常变化是导致IUGR仔猪炎症反应逐级放大以及肠、肝损伤恶性循环的关键环节。清道夫受体A（SR-A）具有调节枯否细胞功能与炎症反应等作用，有望成为营养调控的干预靶点。因此，本研究系统解析了SR-A天然配体岩藻多糖对枯否细胞、肝脏代谢、肠道屏障及微生物区系的影响，初步阐明了岩藻多糖对IUGR断奶仔猪肠肝轴的保护效果和作用机制。主要结果如下：（1）通过基因干扰发现，敲减SR-A表达会抑制岩藻多糖对炎症微环境下枯否细胞吞噬指数、极化分化标志物表达水平、促炎性细胞因子分泌及细胞凋亡水平的调节作用，表明SR-A是IUGR仔猪枯否细胞发挥功能的关键因子；（2）岩藻多糖在断奶仔猪日粮中的最适添加剂量为250 ppm，可改善断奶仔猪肠道和肝脏损伤；（3）岩藻多糖可改善IUGR导致的断奶仔猪饲料效率降低、肠道和肝脏受损，胆汁酸靶向代谢组学和微生物宏基因组学分析结果表明，岩藻多糖可调节肠道微生物的组成和胆汁酸代谢功能，缓解IUGR造成的仔猪肠道脱氧胆酸、熊脱氧胆酸水平的异常降低。本研究结果为改善IUGR断奶仔猪肠肝轴功能与健康状况提供新靶点和新思路。