Lang Hongmei, Xiang Jie, Chen Xiaorong, Tong Dan, Wang Lijuan, Mou Aidi, Liu Daoyan, Gao Peng, Lu Zongshi, Zhu Zhiming
Department of General Medicine, Chengdu Second People's Hospital, Chengdu, People's Republic of China.
Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, Chongqing Institute of Hypertension, Chongqing, People's Republic of China.
Am J Physiol Endocrinol Metab. 2025 Feb 1;328(2):E148-E160. doi: 10.1152/ajpendo.00248.2024. Epub 2024 Dec 16.
Diabetic kidney disease (DKD) is a severe diabetic microvascular complication featured by chronic low-grade inflammation. Roux-en-Y gastric bypass (RYGB) surgery has gained importance as a safe and effective surgery to treat DKD. Bile acids significantly change after RYGB, which brings a series of metabolic benefits, but the relationship with the improvement of DKD is unclear. Therefore, this study performed RYGB surgery on mice to observe the beneficial effects of the surgery on the kidneys and performed bile acid-targeted metabolomics analysis to explore bile acid changes. We found that RYGB significantly reduced albuminuria in mice, improved renal function, reversed renal structural lesions, and attenuated podocyte injury and inflammation. Notably, bile acid metabolomic analysis revealed taurolithocholic acid (TLCA) as the most significantly altered bile acid after RYGB. Furthermore, in vitro and in vivo validation experiments revealed that TLCA supplementation improved renal function and reduced renal inflammatory damage in mice. In addition, TLCA inhibited high glucose-induced inflammatory damage in MPC-5 cells, and its mechanism of action may be related to activating Takeda G protein-coupled receptor 5 (TGR5), inhibiting NF-κB phosphorylation, and thus inhibiting inflammatory response. In conclusion, RYGB may play a protective role in the kidneys of diabetic mice by activating the TLCA/TGR5 pathway. This study determined that the renal protective effect of Roux-en-Y gastric bypass (RYGB) in mice was associated with elevated serum TLCA. Notably, TLCA supplementation improved renal function and alleviated podocyte inflammatory injury in mice, which was associated with the TGR5/NF-κB pathway.
糖尿病肾病（DKD）是一种以慢性低度炎症为特征的严重糖尿病微血管并发症。胃旁路术（RYGB）作为一种治疗DKD的安全有效手术，已变得越来越重要。RYGB术后胆汁酸会发生显著变化，这带来了一系列代谢益处，但与DKD改善之间的关系尚不清楚。因此，本研究对小鼠进行RYGB手术，观察该手术对肾脏的有益作用，并进行胆汁酸靶向代谢组学分析以探索胆汁酸变化。我们发现RYGB显著降低了小鼠蛋白尿，改善了肾功能，逆转了肾脏结构损伤，并减轻了足细胞损伤和炎症。值得注意的是，胆汁酸代谢组学分析显示，牛磺石胆酸（TLCA）是RYGB术后变化最显著的胆汁酸。此外，体外和体内验证实验表明，补充TLCA可改善小鼠肾功能并减少肾脏炎症损伤。此外，TLCA抑制高糖诱导的MPC - 5细胞炎症损伤，其作用机制可能与激活武田G蛋白偶联受体5（TGR5）、抑制NF - κB磷酸化从而抑制炎症反应有关。总之，RYGB可能通过激活TLCA/TGR5途径对糖尿病小鼠肾脏发挥保护作用。本研究确定，胃旁路术（RYGB）对小鼠的肾脏保护作用与血清TLCA升高有关。值得注意的是，补充TLCA可改善小鼠肾功能并减轻足细胞炎症损伤，这与TGR5/NF - κB途径有关。
