He Peishi, He Haoqing, Su Chang, Liu Yarui, Wang Jiahan, Wu Yun, Wang Bing, Wang Shuhong, Zhao Jie
Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
NMPA Key Laboratory for Quality Research and Evaluation of Traditional Chinese Medicine, Shenzhen Key Laboratory of Drug Quality Standard Research, Shenzhen Institute for Drug Control, Shenzhen, Guangdong, 518103, China.
J Ethnopharmacol. 2025 Jan 31;340:119217. doi: 10.1016/j.jep.2024.119217. Epub 2024 Dec 11.
Amomum villosum Lour. (AVL), a traditional Chinese medicine, is widely used to pregnancy-related vomiting and prevent miscarriage. Pre-eclampsia (PE) is a severe pregnancy syndrome. Recent studies have demonstrated interactions between PE and the digestive system. However, it is uncertain that AVL against PE was associated with the gut.
The current research examined the curative impact of AVL on PE and underly mechanisms based on the gut-placenta axis.
A water decoction of AVL (WOA) was extracted in boiling water, and then the decoction was converted into dried particles by freeze drying. An NG-nitro-L-arginine methyl ester (L-NAME)-induced PE mouse model was established and the preventative activity of WOA was evaluated. Furthermore, the gut microbial composition and structure were analyzed using 16S rRNA gene sequencing. Fecal microbiota transplantation (FMT) experiment was applied to confirm the efficacy of gut microbiota remodeled by WOA.
WOA presented protective efficacy against PE. Notably, WOA induced a significant decrease in maternal hypertension and urine protein levels and promoted fetal intrauterine growth in a dose-dependent manner, thereby improving adverse pregnancy outcomes. Moreover, WOA modulated the angiogenic imbalance by decreasing the ratio between sFlt-1 (soluble fms-like tyrosine kinase 1) and PlGF (placental growth factor) to repair placental injury and inhibited placental ferroptosis by increasing the protein levels of FPN1, FTH1, xCT, and GPX4. Tight junction proteins (ZO-1, Occludin, Claudin1) in the placenta and colon were significantly upregulated by WOA, leading to enhanced placental and gut barriers. WOA rescued intestinal dysbiosis by enriching Bifidobacterium and Akkermansia. Fecal microbiota transplantation (FMT) experiments revealed that the protection of WOA on placenta and gut were dependent on the gut microbial composition. Furthermore, supplementation with both Bifidobacterium bifidum (B. bifidum) and vanillic acid (VA, the major component of WOA) ameliorated PE symptoms. Intriguingly, results from both in vivo and in vitro analyses indicated that the B. bifidum population was enriched by VA.
This research is the first to demonstrate that WOA prevents PE by enriching Bifidobacterium bifidum, strengthening the gut-placenta barrier, and inhibiting placental ferroptosis. Our findings provide compelling evidence for the vital involvement of the gut-placental axis in the protection of AVL on PE, presenting a novel target for the clinic.
中药砂仁广泛用于治疗妊娠相关呕吐和预防流产。子痫前期（PE）是一种严重的妊娠综合征。最近的研究表明PE与消化系统之间存在相互作用。然而，砂仁抗PE是否与肠道有关尚不确定。
本研究基于肠-胎盘轴探讨砂仁对PE的治疗作用及其潜在机制。
将砂仁水煎液（WOA）在沸水中提取，然后通过冷冻干燥转化为干颗粒。建立Nω-硝基-L-精氨酸甲酯（L-NAME）诱导的PE小鼠模型，评价WOA的预防活性。此外，采用16S rRNA基因测序分析肠道微生物组成和结构。应用粪便微生物群移植（FMT）实验证实WOA重塑肠道微生物群的功效。
WOA对PE具有保护作用。值得注意的是，WOA能显著降低母体高血压和尿蛋白水平，并以剂量依赖的方式促进胎儿宫内生长，从而改善不良妊娠结局。此外，WOA通过降低可溶性fms样酪氨酸激酶1（sFlt-1）与胎盘生长因子（PlGF）之间的比例来调节血管生成失衡，修复胎盘损伤，并通过增加FPN1、FTH1、xCT和GPX4蛋白水平抑制胎盘铁死亡。WOA显著上调胎盘和结肠中的紧密连接蛋白（ZO-1、Occludin、Claudin1），从而增强胎盘和肠道屏障。WOA通过富集双歧杆菌和阿克曼氏菌来挽救肠道菌群失调。粪便微生物群移植（FMT）实验表明，WOA对胎盘和肠道的保护作用依赖于肠道微生物组成。此外，补充双歧双歧杆菌（B. bifidum）和香草酸（VA，WOA的主要成分）可改善PE症状。有趣的是，体内和体外分析结果均表明VA可富集双歧双歧杆菌。
本研究首次证明WOA通过富集双歧双歧杆菌、加强肠-胎盘屏障和抑制胎盘铁死亡来预防PE。我们的研究结果为肠-胎盘轴在砂仁对PE保护中的重要作用提供了有力证据，为临床提供了一个新的靶点。
