Classical and mediterranean-modified ketogenic diets distinctly shape the gut microbiota composition and function in scopolamine-induced cognitive impairment model

Background Mild cognitive impairment (MCI) is associated with impaired cerebral glucose metabolism, and ketogenic diets may influence cognitive impairment (CI) via the gut-brain axis. We investigated whether classical ketogenic (KD) and Mediterranean-modified ketogenic diet (MMKD) differentially affect gut microbiome composition and function, as well as cognitive performance, in a rat model of scopolamine-induced CI. Methods Twenty-eight male Wistar rats were assigned to a cognitively normal control group (CN), a scopolamine-induced CI group (SCOP) on standard diet, and two scopolamine-treated groups receiving either a classical KD (KD; 84% fat, 16% protein) or a MMKD (60% fat, predominantly olive oil, 30% protein, 10% carbohydrate, resveratrol, and inulin-supplemented) for 9 weeks. Spatial and recognition memory were assessed using the Morris Water Maze and Novel Object Recognition Test. Caecal microbiome composition and function were profiled by shotgun metagenomic sequencing. Short-chain fatty acid (SCFA) analysis was conducted from caecal contents of rats. Brain and hippocampal brain derived neurotrophic factor (BDNF) and phosphorylated cyclic AMP response element-binding (p-CREB) protein levels were evaluated by Western blotting. Results MMKD significantly improved spatial memory relative to other groups. MMKD had higher alpha diversity in the gut microbiome compared to the KD group. KD showed the most distinct gut microbiome profile, marked by enrichment of Bacteroides and Parabacteroides species and reduced carbohydrate and amino acid metabolism. MMKD was characterized by enrichment of lactic acid bacteria with elevated coenzyme A and pyrimidine biosynthesis. Moreover, MMKD was associated with higher SCFA levels compared to the KD group. No significant differences in brain or hippocampal BDNF or p-CREB protein levels were observed among groups. Conclusion These findings show that KD and MMKD produce distinct gut microbiome compositional and functional signatures, with MMKD associated with higher microbial diversity, SCFA levels, and spatial learning performance.