Diosmin alleviates colitis by inhibiting PANoptosis of intestinal epithelial cells and regulating gut microbiota and metabolites

IF 6.7 1区 医学 Q1 CHEMISTRY, MEDICINAL
Cheng Tan , Zixuan Xiang , Shuo Wang , Haodong He , Xiangyun Li , Miao Xu , Xingzhou Guo , Yu Pu , Junhai Zhen , Weiguo Dong
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引用次数: 0

Abstract

Background

Inflammatory bowel disease (IBD), particularly ulcerative colitis (UC), is a chronic inflammatory disorder characterized by an unclear etiology, often linked to gut microbiota dysbiosis and immune dysregulation. Existing UC therapies are constrained by suboptimal efficacy and adverse effects, underscoring the necessity for novel therapeutic strategies. Diosmin (DIO), a naturally occurring flavonoid, has demonstrated anti-inflammatory and antioxidant potential, yet its precise mechanisms and therapeutic role in colitis remain poorly understood.

Purpose

This study aimed to investigate the therapeutic efficacy and mechanistic underpinnings of DIO in dextran sulfate sodium (DSS)-induced colitis, with a focus on its effects on intestinal epithelial cell PANoptosis, gut microbiota composition, fecal metabolites, and an in vitro inflammatory model using human colonic epithelial cells.

Study Design

A controlled experimental design was employed, utilizing a DSS-induced murine colitis model and an LPS-induced inflammatory model in human colonic epithelial cells (NCM460). Mice were allocated into four groups: normal control, DSS-induced colitis, low-dose DIO (DIO-L, 100 mg/kg), and high-dose DIO (DIO-H, 200 mg/kg). In vitro experiments involved treating NCM460 cells with varying DIO concentrations post-LPS stimulation to assess its impact on inflammation and epithelial barrier integrity.

Methods

Mice were administered DIO orally at 100 mg/kg or 200 mg/kg daily. Therapeutic outcomes were evaluated through body weight monitoring, Disease Activity Index (DAI) scoring, and histopathological examination. Gut microbiota composition was analyzed via 16S rRNA sequencing, while untargeted metabolomics was employed to profile fecal metabolites. Data integration was performed using O2PLS and WGCNA to identify microbiota-metabolite correlations. In vitro, immunofluorescence staining and Western blotting were utilized to evaluate the expression of tight junction proteins (ZO-1, E-cadherin, and Occludin).

Results

DIO administration significantly ameliorated colitis symptoms in mice, as evidenced by attenuated weight loss, reduced DAI scores, and preserved colon length. Histopathological analysis confirmed diminished inflammation and tissue damage in DIO-treated groups. Mechanistically, DIO suppressed the expression of PANoptosis-associated genes and proteins, including ZBP1 and Caspase-1, while maintaining epithelial barrier integrity in vitro. Furthermore, DIO modulated gut microbiota composition, promoting beneficial taxa such as Ruminococcus and reducing pathogenic Proteobacteria. Metabolomic profiling revealed alterations in key metabolic pathways, including flavonoid and steroid hormone biosynthesis, which correlated with microbiota changes.

Conclusion

DIO effectively mitigates DSS-induced colitis by inhibiting intestinal epithelial cell PANoptosis, preserving barrier function, and modulating gut microbiota and metabolite profiles. These findings highlight DIO's potential as a therapeutic agent for IBD and warrant further exploration of its clinical applications.

Abstract Image

地奥司明通过抑制肠上皮细胞PANoptosis和调节肠道菌群及代谢物减轻结肠炎
背景:炎症性肠病(IBD),尤其是溃疡性结肠炎(UC),是一种慢性炎症性疾病,其病因尚不清楚,通常与肠道菌群失调和免疫失调有关。现有的UC治疗受到次优疗效和不良反应的限制,强调了新的治疗策略的必要性。地奥司明(DIO)是一种天然存在的类黄酮,具有抗炎和抗氧化的潜力,但其在结肠炎中的确切机制和治疗作用尚不清楚。目的探讨DIO对葡聚糖硫酸钠(dextran sulfate sodium, DSS)诱导的结肠炎的治疗效果和机制基础,重点研究DIO对肠上皮细胞PANoptosis、肠道菌群组成、粪便代谢物的影响,以及对人结肠上皮细胞体外炎症模型的影响。研究设计采用对照实验设计,采用dss诱导的小鼠结肠炎模型和lps诱导的人结肠上皮细胞炎症模型(NCM460)。将小鼠分为正常对照组、dss诱导结肠炎组、低剂量DIO (DIO- l, 100 mg/kg)组和高剂量DIO (DIO- h, 200 mg/kg)组。体外实验包括在lps刺激后用不同浓度的DIO处理NCM460细胞,以评估其对炎症和上皮屏障完整性的影响。方法小鼠口服DIO,剂量分别为100mg /kg和200mg /kg。通过体重监测、疾病活动指数(DAI)评分和组织病理学检查来评估治疗结果。通过16S rRNA测序分析肠道微生物群组成,而非靶向代谢组学用于分析粪便代谢物。使用O2PLS和WGCNA进行数据整合,以确定微生物群-代谢物的相关性。体外免疫荧光染色和Western blotting检测紧密连接蛋白(ZO-1、E-cadherin、Occludin)的表达。结果dio显著改善了小鼠结肠炎症状,减轻了体重减轻,降低了DAI评分,保留了结肠长度。组织病理学分析证实,dio治疗组炎症和组织损伤减轻。在机制上,DIO抑制panoposis相关基因和蛋白的表达,包括ZBP1和Caspase-1,同时在体外维持上皮屏障的完整性。此外,DIO调节肠道菌群组成,促进有益菌群如瘤胃球菌,减少致病变形菌群。代谢组学分析揭示了关键代谢途径的改变,包括黄酮类化合物和类固醇激素的生物合成,这与微生物群的变化有关。结论dio通过抑制肠上皮细胞PANoptosis,保护屏障功能,调节肠道菌群和代谢物谱,有效减轻dss诱导的结肠炎。这些发现突出了DIO作为IBD治疗药物的潜力,值得进一步探索其临床应用。
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来源期刊
Phytomedicine
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.
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