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Blockade of PI3K/AKT signaling pathway by Astragaloside IV attenuates ulcerative colitis via improving the intestinal epithelial barrier
黄芪甲苷IV通过阻断PI3K/AKT信号通路来改善肠上皮屏障减轻UC Journal of Translational Medicine Abstract Background The specific pathogenesis of UC is still unclear, but it has been clear that defects in intestinal barrier function play an important role in it. There is a temporary lack of specific drugs for clinical treatment. Astragaloside IV (AS-IV) is one of the main active ingredients extracted from Astragalus root and is a common Chinese herbal medicine for the treatment of gastrointestinal diseases. This study aimed to determine whether AS-IV has therapeutic value for DSS or LPS-induced intestinal epithelial barrier dysfunction in vivo and in vitro and its potential molecular mechanisms.目前尚不清楚UC具体发病机制，但肠道屏障功能缺陷在其中起着重要作用，目前暂时缺乏临床治疗的特效药。黄芪甲苷IV（AS-IV）是从黄芪中提取的主要活性成分之一，是治疗胃肠道疾病的常用中草药。本研究旨在确定AS-IV在体内外对DSS或LPS诱导的肠上皮屏障功能障碍是否具有治疗价值及其潜在的分子机制。The intestinal tissues from UC patients and colitis mice were collected, intestinal inflammation was observed by colonoscopy, and mucosal barrier function was measured by immunofluorescence staining. PI3K/AKT signaling pathway activator YS-49 and inhibitor LY-29 were administered to colitic mice to uncover the effect of this pathway on gut mucosal barrier modulation. Then, network pharmacology was used to screen Astragaloside IV (AS-IV), a core active component of the traditional Chinese medicine Astragalus membranaceus. The potential of AS-IV for intestinal barrier function repairment and UC treatment through blockade of the PI3K/AKT pathway was further confirmed by histopathological staining, FITC-dextran, transmission electron microscopy, ELISA, immunofluorescence, qRT-PCR, and western blotting. Finally, 16 S rRNA sequencing was performed to uncover whether AS-IV can ameliorate UC by regulating gut microbiota homeostasis.收集UC患者和结肠炎小鼠的肠道组织，通过结肠镜检查观察肠道炎症，并通过免疫荧光染色测量黏膜屏障功能。对结肠炎小鼠给予PI3K/AKT信号通路激活剂YS-49和抑制剂LY-29，以揭示该通路对肠黏膜屏障调节的影响。然后，运用网络药理学方法对中药黄芪的核心活性成分黄芪甲苷IV（AS-IV）进行筛选。通过组织病理学染色、FITC-葡聚糖、透射电子显微镜、ELISA、免疫荧光、qRT-PCR和蛋白质印迹，进一步证实AS-IV通过阻断PI3K/AKT通路修复肠道屏障功能和治疗UC的潜力。最后，进行16S rRNA测序，以揭示AS-IV是否可以通过调节肠道微生物群稳态来改善UC。Mucosal barrier function was significantly damaged in UC patients and murine colitis, and the activated PI3K/AKT signaling pathway was extensively involved. Both in vivo and vitro showed that the AS-IV-treated group significantly relieved inflammation and improved intestinal epithelial permeability by inhibiting the activation of the PI3K/AKT signaling pathway. In addition, microbiome data found that gut microbiota participates in AS-IV–mediated intestinal barrier recovery as well.UC患者和小鼠结肠炎的黏膜屏障功能显著受损，激活的PI3K/AKT信号通路广泛参与。体内外均显示，AS IV治疗组通过抑制PI3K/AKT信号通路的激活，显著缓解炎症并改善肠上皮通透性。此外，微生物组数据发现，肠道微生物群也参与AS-IV介导的肠道屏障恢复。Our study highlights that AS-IV exerts a protective effect on the integrality of the mucosal barrier in UC based on the PI3K/AKT pathway, and AS-IV may serve as a novel AKT inhibitor to provide a potential therapy for UC.研究强调，AS-IV基于PI3K/AKT通路对UC黏膜屏障的完整性发挥保护作用，AS-IV可能作为一种新的AKT抑制剂为UC提供潜在的治疗方法。Graphical abstract 
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