S-9-PAHSA Protects Against High-Fat Diet-Induced Diabetes-Associated Cognitive Impairment via Gut Microbiota Regulation

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2025-05-05 DOI:10.1111/cns.70417

Shanshan Huang, Xinru Wang, Meng Wang, Jinhong Lin, Jiaoqi Ren, Chenyu Lu, Jiayu Fu, Yanli Zhang, Xuechun Wang, Jichang Xiao, Jingchun Guo, Houguang Zhou

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Abstract

Aim

Diabetes-associated cognitive impairment (DACI) is a common complication of Type 2 diabetes mellitus (T2DM), with its mechanisms and treatments for DACI remaining incompletely clarified. This study investigated the protective efficacy of the novel lipid S-enantiomer of 9-palmitic acid esters of hydroxy stearic acids (S-9-PAHSA, S9P) in a high-fat diet-induced DACI mouse model.

Methods

Mice were randomly assigned to three groups: normal diet (ND), high-fat diet (HFD), and HFD + 30 mg/kg/day S9P (HFD + S9P). Fasting blood glucose (FBG), intraperitoneal glucose tolerance test (IPGTT), and insulin tolerance test (ITT) were conducted to assess blood glucose homeostasis. Morris Water Maze and Y maze tests evaluated cognitive function, and neuronal status was examined through pathological analysis, Golgi staining, and transmission electron microscopy (TEM). Colonic barrier integrity was assessed using periodic acid–Schiff and Alcian blue staining (AB-PAS) and immunohistochemistry (IHC) staining. Intestinal microbiota composition was analyzed by 16S rDNA sequencing, and serum metabolic characteristics were determined by metabolomics sequencing.

Results

S9P improved glucose homeostasis and alleviated cognitive decline in DACI mice. It also mitigated neuronal damage, dendritic degeneration, and synaptic damage, while restoring colonic barrier integrity and ameliorating gut microbiome imbalances, insulin resistance, and lipid imbalance. Additionally, S9P regulated metabolite profiles and the PI3K/AKT/mTOR signaling pathways, and reduced astrocyte activation and neuroinflammatory responses in the hippocampus of HFD-induced DACI mice.

Conclusion

S9P had a protective effect against HFD-induced diabetic cognitive impairment closely related to the modulation of the gut–brain axis, suggesting that S9P has the potential to become a new therapeutic approach for DACI.

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S-9-PAHSA通过肠道菌群调节防止高脂肪饮食引起的糖尿病相关认知障碍

目的糖尿病相关认知障碍（DACI）是2型糖尿病（T2DM）的常见并发症，其机制和治疗尚不完全清楚。本研究探讨了新型脂质s -对体羟基硬脂酸9-棕榈酸酯（S-9-PAHSA, S9P）对高脂饮食诱导的DACI小鼠模型的保护作用。方法将小鼠随机分为正常饮食（ND）、高脂饮食（HFD）和高脂饮食+ 30 mg/kg/d S9P (HFD + S9P) 3组。采用空腹血糖（FBG）、腹腔葡萄糖耐量试验（IPGTT）和胰岛素耐量试验（ITT）评估血糖稳态。Morris水迷宫和Y迷宫测试评估认知功能，并通过病理分析、高尔基染色和透射电子显微镜（TEM）检查神经元状态。采用周期性酸-希夫和阿利新蓝染色（AB-PAS）和免疫组织化学（IHC）染色评估结肠屏障的完整性。采用16S rDNA测序分析肠道菌群组成，代谢组学测序测定血清代谢特征。结果S9P改善DACI小鼠葡萄糖稳态，减轻认知能力下降。它还可以减轻神经元损伤、树突变性和突触损伤，同时恢复结肠屏障的完整性，改善肠道微生物群失衡、胰岛素抵抗和脂质失衡。此外，S9P调节代谢物谱和PI3K/AKT/mTOR信号通路，降低hfd诱导的DACI小鼠海马的星形胶质细胞激活和神经炎症反应。结论S9P对hfd诱导的糖尿病认知功能障碍具有保护作用，其机制与肠脑轴调节密切相关，S9P有可能成为治疗DACI的新途径。

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

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.