National Engineering Research Center of TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210029, China.
J Ethnopharmacol. 2025 Jan 30;337(Pt 1):118700. doi: 10.1016/j.jep.2024.118700. Epub 2024 Aug 23.
Zexie-Baizhu Decoction (AA), a Chinese Classical Formula composed of Alisma orientalis (Sam.) Juzep. and Aractylodes Macrocephala Koidz in the specific ratio of 5:2, has a long history of use in treating metabolic disorders. Recent studies have demonstrated AA's ameliorative effects on non-alcoholic fatty liver disease (NAFLD); however, the mechanism underlying its action on the gut and adipose tissue, key regulators of metabolism, have not been fully explored.
This study aimed to investigate the mechanisms by which AA regulates the homeostasis of gut and adipose tissue in NAFLD.
AA (1500 mg/kg/day) or vehicle was administrated to the high-fat diet-induced and normal chow-fed mice (C57BL/6J). Plasma, the liver, gut microbiota, bile acids, and short-chain fatty acids in the gut, were systematically investigated. RNA sequencing analysis, reverse transcription quantitative real-time PCR, and Western Blotting were performed on the epididymal white adipose tissues (eWAT) to explore AA's influence on NAFLD. Lipidomics of the liver and eWAT were analyzed by liquid chromatography-mass spectrometry and desorption electrospray ionization mass spectrometry imaging.
Our study demonstrated that AA administration effectively alleviated liver injury induced by NAFLD, as evidenced by reduced hepatic fat accumulation and inflammation. Mechanistically, AA modulated the composition of the gut microbiota, promoting the growth of beneficial bacteria such as Akkermansia muciniphila and restoring the balance between Firmicutes and Bacteroidetes. Furthermore, AA regulated the levels of bile acids and short-chain fatty acids in the intestine, plasma, and liver. Correspondingly in the eWAT, AA administration activated bile acid receptor (Gpbar1) and short-chain fatty acid receptor (Ffar2), facilitating lipid breakdown and attenuating triglyceride accumulation. Transcriptome analysis revealed that AA influenced gene expression related to fatty acid metabolism, thermogenesis, insulin resistance, AMPK signaling, and the tricarboxylic acid (TCA) cycle, thereby improving NAFLD at the transcriptional level. Additionally, AA treatment significantly altered the lipid composition in the liver, reducing levels of diacylglycerols, triacylglycerols, phosphatidylserines, and cholesterol esters, while increasing levels of phosphatidic acids, phosphatidylethanolamines, and sphingomyelins.
Our study builds a connection between the gut and adipose tissue to understand the mechanism of AA on alleviating NAFLD, providing new insights into the development of targeted therapies for this condition.
泽泻白术汤（AA）是一种由泽泻（Alisma orientalis（Sam.）Juzep.）和白术（Aractylodes macrocephala Koidz）按 5:2 的特定比例组成的中药经典方剂，在治疗代谢紊乱方面有着悠久的应用历史。最近的研究表明，AA 对非酒精性脂肪性肝病（NAFLD）有改善作用；然而，其对肠道和脂肪组织（代谢的关键调节剂）作用的机制尚未得到充分探索。
本研究旨在探讨 AA 调节 NAFLD 肠道和脂肪组织平衡的机制。
用高脂肪饮食诱导和正常饲料喂养的 C57BL/6J 小鼠（AA 或载体）给予 AA（1500mg/kg/天）。系统研究血浆、肝脏、肠道微生物群、胆汁酸和肠道短链脂肪酸。对附睾白色脂肪组织（eWAT）进行 RNA 测序分析、逆转录定量实时 PCR 和 Western Blotting，以探讨 AA 对 NAFLD 的影响。通过液相色谱-质谱和解吸电喷雾电离质谱成像分析肝和 eWAT 的脂质组学。
我们的研究表明，AA 给药可有效缓解 NAFLD 引起的肝损伤，表现为肝脂肪堆积和炎症减少。从机制上讲，AA 调节了肠道微生物群的组成，促进了有益细菌（如阿克曼氏菌属粘液菌）的生长，恢复了厚壁菌门和拟杆菌门之间的平衡。此外，AA 调节了肠道、血浆和肝脏中的胆汁酸和短链脂肪酸水平。相应地，在 eWAT 中，AA 给药激活了胆汁酸受体（Gpbar1）和短链脂肪酸受体（Ffar2），促进脂肪分解，减轻甘油三酯堆积。转录组分析表明，AA 影响与脂肪酸代谢、生热、胰岛素抵抗、AMPK 信号转导和三羧酸（TCA）循环相关的基因表达，从而在转录水平上改善 NAFLD。此外，AA 处理显著改变了肝脏的脂质组成，降低了二酰基甘油、三酰基甘油、磷脂酰丝氨酸和胆固醇酯的水平，同时增加了磷脂酸、磷脂酰乙醇胺和神经鞘磷脂的水平。
本研究将肠道和脂肪组织联系起来，以了解 AA 缓解 NAFLD 的机制，为开发针对这种疾病的靶向治疗提供了新的思路。
