Dietary Methionine Restriction Alleviates Cognitive Impairment in Alzheimer’s Disease Mice via Sex-Dependent Modulation on Gut Microbiota and Tryptophan Metabolism: A Multiomics Analysis
Yuyu Zhang, Tianqi Liu, Fei Pan, Yiju Li, Da Wang, Jingxi Pang, Haojie Sang, Yujia Xi, Lin Shi, Zhigang Liu
Abstract
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 α (PPARα) 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 PPARα signaling to improved cognitive outcomes. Molecular docking and RT-qPCR analyses confirmed IPA’s interaction with PPARα, leading to the activation of neuroprotective targets ( Bdnf, Ppar α, 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.