Dietary fiber modulates gut microbiota and lipid metabolism ameliorating Alzheimer’s pathology in 5xFAD mice

The gut-brain axis plays a critical role in maintaining neuronal integrity and influencing the progression of Alzheimer's disease (AD). Here, we investigated how commonly consumed dietary fibers modulate gut microbiota, lipid metabolism, and AD pathology in 5xFAD mice. Male mice were fed either fiber-free (FF) or fiber-plus (FP; 1% cellulose, 2% pectin, 2% inulin) diets for five months, followed by integrated analyses of gut microbiota (16 S rRNA sequencing), fecal lipid metabolites (LC-MS/MS), and neuropathological and behavioral outcomes. FP diets markedly altered microbial composition, characterized by increases in Muribaculaceae, Ileibacterium, and Lachnospiraceae NK4A136 group and reductions in Faecalibaculum and Coriobacteriaceae UCG-002. Fecal lipidomics revealed significant shifts in phospholipids and long-chain fatty acids, while short-chain fatty acid levels showed only modest, taxa-specific changes. Functionally, FP-fed AD mice exhibited reduced amyloid-beta (Aβ) deposition, lower microglial activation, improved microglial morphology, and a decreased cortical and hippocampal Aβ42/Aβ40 ratio. Moreover, FP diets enhanced hippocampal neurogenesis, preserved synaptic protein expression, and improved cognitive performance in object recognition and Y-maze tasks. FP supplementation also mitigated the increased intestinal permeability observed in AD mice. Together, these findings demonstrate that dietary fiber modulates the microbiome-lipid axis and attenuates AD-related pathology through mechanisms extending beyond SCFA production, supporting dietary interventions as a promising strategy for AD prevention and therapy.