基于肠道菌群-肠肾轴TLR4信号通路探讨大黄结肠给药改善慢性肾衰作用机制的研究

As the “chronic kidney disease (CKD) - colon axis” pointed out, gut-derived inflammation plays an important role in the development of CKD; and that flora disturbance in the colon is considered as an initial trigger while injury of gut barrier is one of the key processes. Therefore, effective regulation of the flora balance might be of great importance to change the CKD progression. Our previous study (NSFC81202819) have demonstrated that colon-administered Rhubarb improves the inflammatory - oxidative stress injury in the kidney of CKD rats, which might be linked to the effect on the gut flora regulation. However, detailed mechanism remains unclear, which limits further study in this field. Based on these findings and novel techniques of metagenomics and fecal microbiota transplantation, we will screen the related bacteria, functional genes and metabolic pathways of CRF treated intestinal flora by colon-administered Rhubarb, and compared with the results of metabolomics, to discover the underlying the mechanism of how colon-administered Rhubarb reducing intestinal endotoxin, improving intestinal mucosal barrier injury and alleviating the inflammation of CRF system was performed by regulate intestinal flora disorder. Furthermore, the mechanism of anti-inflammatory and renal protection of colon-administered Rhubarb will be discussed in animal experiments by regulating the TLR4-MyD88-NF-κB signaling pathway associated with gut-kidney axis.This study will further reveal the mechanism of colon-administered Rhubarb for delaying the progression of chronic renal failure.

“慢性肾脏病-结肠轴”理论指出：肠源性毒素和炎症可加重肾衰进展，结肠菌群紊乱是其始动因素、肠粘膜屏障损伤是其核心环节，有效的调节菌群紊乱对延缓肾衰具有重要意义。我们前期研究发现大黄结肠给药可以减轻慢性肾衰的炎症-氧化应激损伤，可能与调节肠道菌群紊乱有关，但其具体机制尚不清楚。鉴于上述肠肾轴理论和前期研究基础，本项目将利用宏基因组学、粪菌移植等新技术，在动物模型上筛选获得大黄结肠给药治疗CRF的相关菌群、功能基因和代谢途径，并和代谢组学的结果进行比对，以明确大黄结肠给药如何通过调节肠道菌群紊乱，从而发挥降低肠源性毒素、改善肠粘膜屏障损伤、减轻CRF系统炎症的作用机制；进一步在动物实验中探讨大黄结肠给药通过调节肠肾轴相关的TLR4-MyD88-NF-κB信号通路发挥抗炎和肾脏保护的作用机制。本研究将较深入的揭示大黄结肠给药延缓慢性肾衰进展的作用机制。

“慢性肾脏病-结肠轴”理论指出：肠源性毒素和炎症可加重肾衰进展，结肠菌群紊乱是其始动因素、肠粘膜屏障损伤是其核心环节，有效的调节菌群紊乱对延缓肾衰具有重要意义。我们前期研究发现大黄结肠给药可以减轻慢性肾衰的炎症-氧化应激损伤，可能与调节肠道菌群紊乱有关，但其具体机制尚不清楚。鉴于上述肠肾轴理论和前期研究基础，本项目将利用宏基因组学、粪菌移植等新技术，在动物模型上筛选获得大黄结肠给药治疗CRF的相关菌群、功能基因和代谢途径，并和代谢组学的结果进行比对，以明确大黄结肠给药如何通过调节肠道菌群紊乱，从而发挥降低肠源性毒素、改善肠粘膜屏障损伤、减轻CRF系统炎症的作用机制；进一步在动物实验中探讨大黄结肠给药通过调节肠肾轴相关的TLR4-MyD88-NF-κB信号通路发挥抗炎和肾脏保护的作用机制。本研究将较深入的揭示大黄结肠给药延缓慢性肾衰进展的作用机制。