Dietary Methionine Restriction Alleviates Cognitive Impairment in Alzheimer's Disease Mice via Sex-Dependent Modulation on Gut Microbiota and Tryptophan Metabolism: A Multiomics Analysis

文献类型： 外文期刊

第一作者： Zhang, Yuyu

作者： Zhang, Yuyu;Li, Yiju;Wang, Da;Pang, Jingxi;Sang, Haojie;Xi, Yujia;Liu, Zhigang;Liu, Tianqi;Shi, Lin;Pan, Fei;Li, Yiju;Liu, Zhigang

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关键词： Alzheimer's disease; methionine restriction; sexual dimorphism; indole-3-propionic acid; peroxisome proliferator-activated receptor alpha; multiomics

期刊名称：JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY （ 影响因子：6.2； 五年影响因子：6.4 ）

ISSN： 0021-8561

年卷期： 2025 年 73 卷 2 期

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收录情况： SCI

摘要： Plant-based foods with low methionine contents have gained increasing interest for their potential health benefits, including neuroprotective effects. Methionine restriction (MR) linked to a plant-based diet has been shown to mitigate neurodegenerative diseases such as Alzheimer's disease (AD) through mechanisms that involve the gut microbiota. In this study, a 16-week MR diet (0.17% methionine, w/w) improved working memory and reduced neuronal damage exclusively in 4-month-old male APP/PS1 AD mice. Transcriptomic analysis revealed the activation of serum- and glucose-corticoid-regulated kinase 1 (SGK1) and peroxisome proliferator-activated receptor alpha (PPAR alpha) pathways. Furthermore, metabolomics demonstrated increased serum indole-3-propionic acid (IPA) levels and an enhanced expression of gut barrier proteins Claudin-1 and MUC2 in male mice. MR significantly altered the gut microbiota composition, notably increasing indole-producing bacteria such as Lactobacillus reuteri (L. reuteri). Multiomics integration linked L. reuteri, IPA, and PPAR alpha signaling to improved cognitive outcomes. Molecular docking and RT-qPCR analyses confirmed IPA's interaction with PPAR alpha, leading to the activation of neuroprotective targets (Bdnf, Ppar alpha, Acsbg1, Scd2, and Scd3). These results highlight the role of methionine restriction in modulating gut microbiota and metabolites, offering a promising dietary approach to managing neurodegenerative diseases with sex-specific effects.

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