Patchouli alcohol restores gut homeostasis in irritable bowel syndrome with diarrhea through myosin Va-mediated neurotransmitter regulation

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-04-09 DOI:10.1016/j.phymed.2025.156681

Wanyu Chen , Ting Li , Yukang Lin , Zijun Chen , Milei OuYang , Ying Pei , Shulin Yi , Shuyan Huang , Zitong Huang , Lu Liao , Na Zhou , Jintong Lu , ZhuoYing Chen , Hongying Cao , Bo Tan

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引用次数: 0

Abstract

Background

Patchouli alcohol (PA), the active ingredient of Pogostemonis Herba, is important in medicine and food, effectively alleviating irritable bowel syndrome with diarrhea (IBS-D) symptoms; however, its mechanism remains unclear. Myosin Va, particularly in the intestinal longitudinal muscle myenteric plexus (LMMP), modulates neurotransmitter release, restoring gastrointestinal motility.

Purpose

To investigate the primary targets and potential mechanisms of PA in the treatment of IBS-D.

Study design

PA treats IBS-D may involve the regulation of neurotransmitter release through the modulation of Myosin Va, and remodels neurons of colon LMMP, ultimately restores enteric nervous system (ENS) homeostasis.

Methods

The GEO database, UK Biobank (UKB) public database and Mendelian randomization (MR) were utilized to identify differentially expressed genes and risk genes in IBS-D population. Network pharmacology and molecular docking were applied to screen for targets of PA in the treatment of IBS-D and predicted the binding affinity of drug targets. We established a chronic restraint stress-induced IBS-D rat model, after that PA (5 mg/kg and 20 mg/kg) was given to treat disease, and multi-omics methods such as bacterial 16S rRNA sequencing, whole transcriptome sequencing and snRNA-seq were used to observe the therapeutic effect of PA. Then measured the expression levels of LMMP neurotransmitter and Myosin Va via in vivo and in vitro experiments. Additionally, observe the effect of PA on Myosin Va-deficient DBA(Dilute, Brown and Non-Agouti) mice, and the regulation of Myosin Va expression by PA was verified by knockdown and overexpression gene function.

Results

Bioinformatics analysis, Mendelian randomization and Network pharmacology suggested that neurotransmitter are PA targets in IBS-D treatment. Molecular docking predicted a strong binding affinity between PA and these targets. Multiomics indicated aberrant gastrointestinal motility, imbalanced excitatory and inhibitory neurons, and significantly reduced myosin Va expression under chronic restraint stress-induced IBS-D rat. PA treatment significantly improved these symptoms and restored intestinal microbiota homeostasis. Ex vivo experiments, DBA mice verification and gene function experiments suggested that PA treatment of IBS-D involves regulation of neurotransmitter release by modulating myosin Va and remodeling colon LMMP neurons, restoring enteric nervous system homeostasis.

Conclusion

Our results provide a theoretical basis for PA application in IBS-D treatment.

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广藿香醇通过肌球蛋白va介导的神经递质调节恢复肠易激综合征腹泻的肠道稳态

广藿香醇（patchouli alcohol， PA）是广藿香的活性成分，具有重要的药用和食用价值，可有效缓解肠易激综合征伴腹泻（IBS-D）症状；然而，其机制尚不清楚。肌球蛋白Va，特别是在肠纵肌肌丛（LMMP）中，调节神经递质释放，恢复胃肠运动。目的探讨PA治疗IBS-D的主要作用靶点及可能机制。研究设计：pa治疗IBS-D可能通过调节Myosin Va调节神经递质释放，重塑结肠lmpp神经元，最终恢复肠神经系统（ENS）稳态。方法采用GEO数据库、UK Biobank （UKB）公共数据库和孟德尔随机化（MR）方法对IBS-D人群差异表达基因和危险基因进行鉴定。应用网络药理学和分子对接技术筛选PA治疗IBS-D的靶点，预测药物靶点的结合亲和力。建立慢性约束应激诱导的IBS-D大鼠模型，给予5 mg/kg和20 mg/kg的PA治疗，采用细菌16S rRNA测序、全转录组测序和snRNA-seq等多组学方法观察PA的治疗效果。然后通过体内和体外实验检测lmpp神经递质和肌球蛋白Va的表达水平。此外，观察PA对Myosin Va缺陷DBA（稀、棕、非agouti）小鼠的影响，通过敲低和过表达基因功能验证PA对Myosin Va表达的调节作用。结果生物信息学分析、孟德尔随机化和网络药理学提示神经递质是肠易激综合征- d治疗中的PA靶点。分子对接预测PA与这些靶点之间具有很强的结合亲和力。多组学结果显示，慢性抑制性应激诱导的IBS-D大鼠胃肠道运动异常，兴奋性和抑制性神经元失衡，肌球蛋白Va表达显著降低。PA治疗可显著改善这些症状并恢复肠道微生物群稳态。离体实验、DBA小鼠验证和基因功能实验表明，PA治疗IBS-D通过调节肌球蛋白Va和重塑结肠LMMP神经元来调节神经递质释放，恢复肠道神经系统稳态。结论本研究结果为PA在IBS-D治疗中的应用提供了理论依据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.