Didang decoction improves gut microbiota and cognitive function in TDACD rats: Combined proteomics and 16S rRNA sequencing

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-04-11 DOI:10.1016/j.phymed.2025.156758

Zihan Li , Caiyi Long , Jiajing Tao , Xi Peng , Ya-yi Jiang , Rensong Yue

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引用次数: 0

Abstract

Background

Type 2 diabetes mellitus (T2DM) significantly elevates the risk of cognitive impairment. Didang Decoction (DDD), a classical Traditional Chinese Medicine (TCM) formula, has shown promise in alleviating diabetic symptoms and improving cognitive performance. Although historical TCM records suggest neuroprotective properties, the mechanistic basis for DDD's therapeutic effects on T2DM-associated cognitive dysfunction (TDACD) remains unexplored.

Purpose

This work sought to clarify the chemical composition and mechanisms of action of DDD by pursuing three primary objectives: (1) identification of the major active constituents of DDD; (2) validating of the hypothesis that DDD ameliorates TDACD via regulation of the gut microbiota; and (3) investigating DDD's regulatory effects on hippocampal lipid metabolism and autophagy pathways.

Methods

Ultra-high performance liquid chromatography-Q exactive mass spectrometry (UHPLC-QE-MS/MS) was employed to analyze the chemical composition of DDD. Cognitive function was assessed through behavioral tests. Histopathological examinations and western blotting (WB) were conducted to assess the effects of DDD on the hippocampus of TDACD rats. 16S ribosomal RNA (16S rRNA) sequencing was conducted to characterize gut microbiota, composition, and proteomics was used to evaluate hippocampal proteins expression.

Results

The major bioactive components of DDD were identified, including dihydrotanshinone I, aloe-emodin, chrysophanol, calycosin, sakuranetin, gallic acid, kaempferol, and rhein, emodin, etc. DDD increased neuronal density and synaptic function in the hippocampus of TDACD rats, hereby improving working memory and long-term memory. DDD boosted the relative abundance of beneficial bacteria, including Roseburia, [Eubacterium] coprostanoligenes group, Christensenellaceae R-7 group, and Alistipes, which were diminished in the TDACD group. Proteomics analysis indicated that DDD enhanced hippocampal energy metabolism and reduced neuronal damage in TDACD rats via pathways related to cholesterol and fatty acid metabolism, as well as autophagy.

Conclusions

DDD demonstrates potential as an adjuvant therapeutic agent for TDACD, with dual benefits in ameliorating glucose metabolism and cognitive impairments. Mechanistically, the neuroprotective effects of DDD are attributed to the regulation of hippocampal lipid energy metabolism and autophagic homeostasis, as well as the enhancement of beneficial gut microbes.

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地当汤改善tddad大鼠肠道菌群和认知功能：联合蛋白质组学和16S rRNA测序

背景：2型糖尿病（T2DM）显著增加认知功能障碍的风险。地当汤（DDD）是一种经典的中药配方，在缓解糖尿病症状和改善认知能力方面表现出了希望。尽管历史上的中医记录表明DDD具有神经保护作用，但DDD治疗t2dm相关认知功能障碍（tddad）的机制基础仍未被探索。本工作旨在通过三个主要目标来阐明DDD的化学成分和作用机制：(1)鉴定DDD的主要有效成分；(2)验证了DDD通过调节肠道菌群改善tddad的假说；(3)研究DDD对海马脂质代谢和自噬通路的调节作用。方法采用超高效液相色谱- q质谱联用（UHPLC-QE-MS/MS）对DDD进行化学成分分析。通过行为测试评估认知功能。采用组织病理学检查和western blotting （WB）方法观察DDD对tddad大鼠海马的影响。16S核糖体RNA （16S rRNA）测序用于表征肠道微生物群，组成，蛋白质组学用于评估海马蛋白表达。结果鉴定出DDD的主要生物活性成分为：二氢丹参酮I、芦荟大黄素、大黄酚、毛蕊异黄酮、樱素、没食子酸、山奈酚、大黄素等。DDD增加tddad大鼠海马神经元密度和突触功能，从而改善工作记忆和长期记忆。DDD提高了有益菌的相对丰度，包括Roseburia， [Eubacterium] coprostanoligenes组，Christensenellaceae R-7组和Alistipes，而tddad组则降低了有益菌的相对丰度。蛋白质组学分析表明，DDD通过与胆固醇和脂肪酸代谢以及自噬相关的途径增强了tddad大鼠的海马能量代谢，减轻了神经元损伤。结论ddd作为tddad的辅助治疗药物具有改善糖代谢和认知功能障碍的双重疗效。从机制上讲，DDD的神经保护作用可归因于调节海马脂质能量代谢和自噬稳态，以及增强有益肠道微生物。

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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.