Chen Dan-Qian, Zhang Hao-Jun, Zhang Wen, Feng Kai, Liu Hui, Zhao Hai-Ling, Li Ping
Faculty of Life Science & Medicine, Northwest University, 229 Taibai North Road, Xi'an 710069, China; Beijing Key Lab for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, 2 Yinghua Dongjie, Beijing 100029, China.
Beijing Key Lab for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, 2 Yinghua Dongjie, Beijing 100029, China.
Exp Gerontol. 2024 Apr;188:112393. doi: 10.1016/j.exger.2024.112393. Epub 2024 Mar 10.
Diabetic kidney disease (DKD) is leading causes and one of the fastest growing causes of chronic kidney disease worldwide, and leads to high morbidity and mortality. Emerging evidences have revealed gut microbiota dysbiosis and related metabolism dysfunction play a dominant role in DKD progression and treatment through modulating inflammation. Our previous studies showed that Tangshen Formula (TSF), a Chinese herbal prescription, exhibited anti-inflammatory effect on DKD, but underlying mechanism that involved gut microbiota and related metabolism in aged model remained obscure. Here, BTBR ob/ob mice were used to establish aged DKD model, and 16S rRNA sequence and untargeted metabolomic analyses were employed to investigate the correlation between colonic microbiota and serum metabolism. The aged ob/ob mice exhibited obvious glomerular and renal tubule injury and kidney function decline in kidney, while TSF treatment significantly attenuated these abnormalities. TSF also exhibited potent anti-inflammatory effect in aged ob/ob mice indicating by reduced proinflammatory factor IL-6 and TNF-α, MCP-1 and COX-2 in serum, kidney and intestine, which suggested the involvement of gut microbiota with TSF effect. The 16S rDNA sequencing of the colonic microbiome and untargeted serum metabolomics analysis revealed significant differences in gut microbiota structure and serum metabolomic profiles between WT and ob/ob mice. Notably, TSF treatment reshaped the structure of gut microbiota and corrected the disorder of metabolism especially tryptophan metabolism and arginine biosynthesis. TSF increased Anaeroplasma and Barnesiella genera and decreased Romboutsia, Akkermansia, and Collinsella genera, and further elevated tryptophan, 5-hydroxyindoleacetate, glutamic acid, aspartate and reduced 4-hydroxy-2-quinolinecarboxylic acid, indole-3-acetic acid, xanthurenic acid, glutamine. Further correlation analysis indicated that disturbed gut microbiota was linked to tryptophan metabolism and arginine biosynthesis to regulate inflammation in aged DKD. Our data revealed that TSF attenuated renal inflammation by modulating gut microbiota and related amino acid metabolism in aged DKD model, highlighting gut microbiota and related metabolism functioned as potential therapeutic target for DKD in elderly patients.
糖尿病肾病（DKD）是全球慢性肾脏病的主要病因之一，且是增长最快的病因之一，会导致高发病率和死亡率。新出现的证据表明，肠道微生物群失调及相关代谢功能障碍通过调节炎症在DKD的进展和治疗中起主导作用。我们之前的研究表明，中药方剂糖肾方（TSF）对DKD具有抗炎作用，但在衰老模型中涉及肠道微生物群及相关代谢的潜在机制仍不清楚。在此，使用BTBR ob/ob小鼠建立衰老DKD模型，并采用16S rRNA序列和非靶向代谢组学分析来研究结肠微生物群与血清代谢之间的相关性。衰老的ob/ob小鼠肾脏出现明显的肾小球和肾小管损伤以及肾功能下降，而TSF治疗显著减轻了这些异常。TSF在衰老的ob/ob小鼠中也表现出强大的抗炎作用，血清、肾脏和肠道中的促炎因子白细胞介素-6、肿瘤坏死因子-α、单核细胞趋化蛋白-1和环氧化酶-2减少，这表明肠道微生物群参与了TSF的作用。结肠微生物组的16S rDNA测序和非靶向血清代谢组学分析显示，野生型和ob/ob小鼠之间肠道微生物群结构和血清代谢组学谱存在显著差异。值得注意的是，TSF治疗重塑了肠道微生物群的结构，并纠正了代谢紊乱，尤其是色氨酸代谢和精氨酸生物合成。TSF增加了厌氧支原体属和巴内西氏菌属，减少了罗姆布茨菌属、阿克曼氏菌属和柯林斯菌属，并进一步提高了色氨酸、5-羟吲哚乙酸、谷氨酸、天冬氨酸，降低了4-羟基-2-喹啉羧酸、吲哚-3-乙酸、黄尿酸、谷氨酰胺。进一步的相关性分析表明，肠道微生物群紊乱与色氨酸代谢和精氨酸生物合成有关，以调节衰老DKD中的炎症。我们的数据表明，TSF通过调节衰老DKD模型中的肠道微生物群和相关氨基酸代谢来减轻肾脏炎症，突出了肠道微生物群和相关代谢作为老年DKD患者潜在治疗靶点的作用。
