基于肠肾轴理论模型探讨大黄结肠给药改善肾间质纤维化的机制研究

Chinese medicine rhubarb enema can effectively prevent chronic renal failure，and widely used in the clinical practice，but the the study on the mechanism is still blank. Our previous clinical study revealed that rhubarb enema .can effectively reduced the serum level of enterogenous urine toxin-indoxyl sulfate which was associated with the advance of chronic renal failure. On the base of it and theory of the gut-kidney axis，we designed the animal research to discuss the effect of rhubarb enema on the intestinal flora，gut barrier，enterogenous urine toxin（indoxyl sulfate and sulfuric acid to cresol）and renal fibrosis of the chronic renal failure model rats，and more the cellular and molecular research to discuss the effect of rhubarb enema on the passway of enterogenous urine toxin-renal tubular epithelial cell oxidatie stress damage-NF/B（p65）to uncover the the cellular and molecular mechanism of preventing tubulointerstitial fibrosis with rhubarb enema. We hope the result of the study can provide the rationale of new strategy of prevent chronic renal failure with TCM intestinal targeted drug.

中药大黄结肠给药能有效的延缓慢性肾功能衰竭进展，在临床上广泛应用，但其作用机制研究几乎还是空白。我们在前期的临床研究中发现大黄结肠给药可以明显降低慢性肾衰患者的血清肠源性尿毒素-硫酸吲哚酚的水平，与延缓慢性肾衰的进展密切相关。在此基础上我们根据尿毒素的肠-肾轴理论模型，观察大黄结肠给药对慢性肾衰模型大鼠肠道菌群、肠源性毒素（硫酸吲哚酚、硫酸对甲酚）的影响；进一步从肠源性毒素-肾小管上皮细胞氧化应激损伤-NF/kB（p65）途径阐释大黄结肠给药改善肾间质纤维化的机制。为进一步探寻中药结肠靶向给药延缓慢性肾衰的防治新策略奠定理论基础。

中药大黄结肠给药在临床上广泛应用于延缓慢性肾功能衰竭进展。然而，大黄结肠给药对慢性肾功能衰竭产生保护作用的具体机制尚不明确。本研究基于肠肾轴理论模型研究大黄结肠给药对慢性肾衰大鼠肠道菌群和肠源性毒素的影响及其对肠源性毒素-氧化应激损伤-NF-κB（p65）途径导致的肾间质纤维化的影响。研究结果表明：1.大黄结肠给药能显著增加慢性肾衰大鼠肠道菌群中的双歧杆菌和乳酸杆菌数量，显著减少大肠埃氏菌的数量及关键肠源性毒素-硫酸吲哚酚的含量；2.大黄结肠给药能显著降低慢性肾衰大鼠血肌酐水平及hs-CRP水平，减轻肾脏组织炎症反应，降低肾组织中collagen I、occludin、8-OHDG及NF-κB（p65）的表达，并提高SOD的水平。本研究表明：中药大黄结肠给药可通过调节肠道菌群，降低肠道菌群代谢毒素硫酸吲哚酚，减轻慢性肾衰大鼠肾组织氧化应激及NF-κB（p65）途径的系统炎症，改善肾小管间质纤维化改变及肾功能，最终发挥延缓慢性肾功能衰竭进展的作用。