Shoutai pill exhibits anti-miscarriage efficacy through tripartite modulation of gut microbiota, systemic metabolism, and maternal-fetal immunity: A multi-omics analysis

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-06-19 DOI:10.1016/j.phymed.2025.156991

Wanfeng Xu , Bo Li , Zhihao Ge , Lu Li , Xinglishang He , Xuannan Chen , Chu Chu , Guiyuan Lv , Suhong Chen

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引用次数: 0

Abstract

Background

Shoutai pill (STP)—a classical Chinese herbal formula—is clinically used to manage miscarriage, albeit its bioactive constituents and pharmacological mechanisms are not incompletely characterized.

Purpose

To elucidate the bioactive components and molecular mechanisms underpinning the efficacy against miscarriage of STP, we integrated spectral analysis with multi-omics profiling (encompassing 16S rRNA sequencing, transcriptomics, and metabolomics) to establish a novel system-to-molecule framework for deciphering the conventional herbal formulations.

Methods

Active components were identified using LC-MS. A miscarriage mouse model was established to evaluate the embryo loss rate, serum estradiol (E₂), and progesterone (P) levels. Spectrum-effect relationship analysis correlated chemical constituents with their efficacy. Mechanistic insights were explored via uterine transcriptomics, 16S rRNA gut microbiota sequencing, serum metabolomics, and molecular validation (qPCR, western blotting, immunohistochemistry).

Results

STP was found to significantly reduce embryo loss and elevate the serum E₂/P levels, with the STP extract (STE) displaying maximal efficacy. Histopathological analysis revealed improved endometrial decidualization in STE-treated mice. Transcriptomics identified 1,476 differentially expressed uterine genes (434 upregulated and 1,042 downregulated), notably suppressing the IL-17-signaling pathway genes. STE upregulated Foxp3 mRNA while downregulating IL-17, RORγt, and NFκB. Western bloting confirmed STE-mediated suppression of IL-17/JAK2/p-STAT3/NFκB/IL-6 axis and induction of Foxp3/IL-10 proteins. Gut microbiota analysis demonstrated that STE improved the composition and abundance of gut microbiota at the phylum and genus levels. Immunohistochemistry validated intestinal Foxp3⁺/IL-10⁺ cell increase and IL-6/RORγt reduction. Metabolomics identified 237 differentially regulated serum metabolites (134 upregulated and 103 downregulated), which were closely associated with gene expressions and microbial abundance.

Conclusion

The anti-miscarriage efficacy of STP was mediated by chlorogenic acid, isochlorogenic acid A, asperosaponin VI, and others. STP administration could restore the gut microbial ecosystem and reprogram the host metabolism. In addition, STP administration normalized the Th17/Treg cell ratio at the maternal-fetal interface through JAK2/STAT3-signaling inhibition, thereby stabilizing immune tolerance during early gestation. The results offer novel insights into the anti-miscarriage mechanism and bioactive components of STP.

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寿泰丸通过调节肠道菌群、全身代谢和母胎免疫，显示抗流产功效：多组学分析

摘要寿太丸是临床上用于治疗流产的经典中药配方，但其生物活性成分和药理机制尚不完全清楚。为了阐明STP抗流产疗效的生物活性成分和分子机制，我们将光谱分析与多组学分析（包括16S rRNA测序、转录组学和代谢组学）相结合，建立了一个新的系统-分子框架，用于破译传统草药配方。方法采用液相色谱-质谱法鉴定有效成分。建立流产小鼠模型，评价胚胎损失率、血清雌二醇（E2）、孕酮(P)水平。光谱效应关系分析将化学成分与其功效联系起来。通过子宫转录组学，16S rRNA肠道微生物群测序，血清代谢组学和分子验证（qPCR, western blotting，免疫组织化学）探索机制见解。结果STP能显著降低胚胎丢失，提高血清E2/P水平，其中STP提取物（STE）效果最好。组织病理学分析显示，经ste治疗的小鼠子宫内膜去个体化得到改善。转录组学鉴定出1476个差异表达的子宫基因（434个上调，1042个下调），显著抑制il -17信号通路基因。STE上调Foxp3 mRNA，下调IL-17、RORγt和NFκB。Western blotting证实ste介导IL-17/JAK2/p-STAT3/NFκB/IL-6轴的抑制和Foxp3/IL-10蛋白的诱导。肠道菌群分析表明，STE在门和属水平上改善了肠道菌群的组成和丰度。免疫组化证实肠道Foxp3+/IL-10+细胞升高，IL-6/ ror γ - t降低。代谢组学鉴定出237种差异调节的血清代谢物（134种上调，103种下调），它们与基因表达和微生物丰度密切相关。结论STP的抗流产作用与绿原酸、异绿原酸A、曲霉皂苷VI等有关。STP可以恢复肠道微生物生态系统，并对宿主代谢进行重编程。此外，STP通过抑制JAK2/ stat3信号通路，使母胎界面的Th17/Treg细胞比例正常化，从而稳定妊娠早期的免疫耐受。该结果为STP的抗流产机制和生物活性成分提供了新的见解。

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.