Gramineae Wheat Germ Extract Ameliorates Methylglyoxal‐Induced Neurobehavioral Deficits Through Modulation of the Gut Microbiota and Tryptophan Metabolism

Emerging evidence highlights the pivotal role of the gut-brain axis (GBA) in the pathogenesis of neurodegenerative diseases, with gut microbiota and tryptophan-derived metabolites acting as key modulators. In this study, we investigated the neuroprotective potential of wheat germ extract (WGE) in a methylglyoxal (MG)-induced neurodegenerative mouse model. Male C57BL/6J mice were randomly assigned into four groups: Control (C), Methylglyoxal (MG, 1% MG in drinking water), GABA (1% MG + 200 mg/kg/day GABA), or WGE (1% MG + 200 mg/kg/day WGE). WGE significantly improved spatial learning, alleviated anxiety-like behaviors, and reduced hippocampal damage and Tau hyperphosphorylation. Moreover, WGE reshaped gut microbiota composition by decreasing the abundance of pathogenic taxa, including Helicobacter hepaticus, Eubacterium plexicaudatum, Lachnospiraceae bacterium TWA4 sp000875945, Ventrisoma, and Oribacterium, while restoring the levels of the beneficial TANB77 bacterium CAG-793 sp000433915. WGE also replenished neuroprotective tryptophan metabolites, particularly indole-3-propionic acid (IPA) and indole-3-lactic acid (ILA), and modulated host functional pathways related to cell motility and epithelial signaling associated with Helicobacter pylori infection. These findings demonstrate that WGE may exert neuroprotective effects by modulating gut microbiota composition and tryptophan metabolism, providing novel insights into GBA-targeted strategies for the prevention of neurodegenerative disorders.