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
作者： Zhang, Yuyu 1 ; Liu, Tianqi 2 ; Pan, Fei 3 ; Li, Yiju 1 ; Wang, Da 1 ; Pang, Jingxi 1 ; Sang, Haojie 1 ; Xi, Yujia 1 ; Shi, Lin 2 ; Liu, Zhigang 1 ;
作者机构： 1.Northwest A&F Univ, Coll Food Sci & Engn, Lab Funct Chem & Nutr Food, Yangling 712100, Shaanxi, Peoples R China
2.Shaanxi Normal Univ, Coll Food Engn & Nutr Sci, Xian 710119, Shaanxi, Peoples R China
3.Chinese Acad Agr Sci, Inst Apicultural Res, State Key Lab Resource Insects, Beijing 100093, Peoples R China
4.Univ Alberta, Agr Forestry Ctr, Dept Agr Food & Nutr Sci, Edmonton, AB T6G2P5, Canada
5.Northwest A&F Univ, Shenzhen Res Inst, Shenzhen 518000, Guangdong, Peoples R China
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
页码：
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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