Nicotinamide mononucleotide supplementation modulates gut microbiota and metabolites to mitigate Alzheimer's disease pathology in APP/PS1 mice

Background Emerging evidence indicates that gut microbiome dysbiosis may be linked to Nicotinamide adenine dinucleotide (NAD + ) deficiency during Alzheimer's disease (AD) progression, a condition potentially alleviated by nicotinamide mononucleotide (NMN) supplementation. Objective To explore the therapeutic potential of NMN supplementation in regulating AD pathology as well as gut microbiome dynamics, APP/PS1 transgenic mouse models were employed in the research. Methods Metagenomic and metabolomics analysis were conducted to assess modifications in the intestinal microbiota and metabolites of AD mice post-NMN treatment. Moreover, immunohistochemistry, immunofluorescence, western blot, and Morris water maze were applied to evaluate NMN's ameliorative effects on AD. Results NMN administration significantly altered gut microbial composition and fecal metabolite profiles, leading to improvements in colon damage and AD-related neuropathology. Key findings include the restoration of gut microbial balance, particularly increasing Bacteroides abundance, and the modulation of metabolites involved in lipid metabolism. Furthermore, NMN was found to regulate ferroptosis, improving gut barrier function in AD mice, which were mediated through gut-brain communication pathways. NMN supplementation also enhanced ATP production, mitochondrial function, and synaptic density in the hippocampus while reducing oxidative stress and Aβ accumulation in the brain. Ultimately, these multi-faceted improvements collectively alleviated cognitive deficits in AD mice. Conclusions In summary, NMN supplementation effectively modulated gut microbiota and metabolites, thus mitigating AD pathology in APP/PS1 mice. Our study offers novel perspectives on the mechanisms underlying NMN's therapeutic effects in AD and underlines its potential as a promising intervention strategy.