Targeting the Gut–Brain Axis: Protective Effects of NMN in Alleviating D-Galactose-Induced Cognitive Deficits

Background: To evaluate the neuroprotective effect of nicotinamide mononucleotide (NMN), an NAD+ precursor, in a D-galactose-induced aging mouse model. Chronic D-galactose administration is widely used to establish age-related cognitive impairment driven by oxidative stress. Methods: Mice received subcutaneous D-galactose for six weeks, concomitantly with oral NMN (300 or 500 mg/kg). Cognitive function was assessed using the Y-maze test and the Elevated Plus Maze test. Oxidative stress indicators, inflammatory cytokines, and Nrf2/HO-1 pathway components were measured by ELISA, Western blotting, and Immunohistochemistry. Gut microbiota composition was analyzed via 16S rRNA sequencing. Results: NMN supplementation improved spatial memory without affecting anxiety-related behavior. NMN enhanced the activities of antioxidant enzymes (SOD, GSH, CAT), reduced malondialdehyde and pro-inflammatory cytokine levels and decreased microglial activation in the hippocampus. Furthermore, NMN remodeled the gut microbiota by increasing butyrate-producing taxa (such as Butyrivibrio_A and Clostridium_T) and activated the Nrf2/HO-1 signaling pathway. Conclusions: NMN alleviates age-related cognitive decline in mice by reducing oxidative stress, suppressing neuroinflammation, and modulating the gut microbiota. Targeting the gut–brain axis and the Nrf2/HO-1 pathway may therefore represent a promising therapeutic strategy for age-related neurodegeneration.