Ketogenic Diet Mitigates Age-Related Cognitive Decline and Neuroinflammation in Rats, While Antibiotics Exacerbate Brain Health Risks.

The ketogenic diet (KD), a high-fat, low-carbohydrate regimen, has been shown to exert neuroprotective effects in various neurological models. This study explored how KD-alone or combined with antibiotic-induced gut microbiota depletion-affects cognition and neuroinflammation in aging. Thirty-two male rats (22 months old) were assigned to four groups (n = 8): control diet (CD), ketogenic diet (KD), antibiotics with control diet (AB), and antibiotics with KD (KDAB). Diets were maintained for 10 weeks; during the final week, AB and KDAB groups received a broad-spectrum antibiotic cocktail (ampicillin 1 g/L, vancomycin 0.5 g/L, neomycin 1 g/L, and metronidazole 1 g/L) in drinking water. Cognitive abilities were evaluated using the Morris Water Maze and Novel Object Recognition Test. BDNF and inflammatory cytokines (TNF-α, IL-1β, IL-10) were measured in the hippocampus and prefrontal cortex. KD and KDAB groups exhibited increased β-hydroxybutyrate and reduced glucose levels, enhanced cognitive performance, elevated BDNF and IL-10, and decreased TNF-α and IL-1β compared to non-KD groups. Although antibiotic treatment alone caused only a transient impairment in spatial memory and was associated with reduced TNF-α levels, the ketogenic diet-irrespective of microbiota status-consistently improved cognitive performance and elevated neuroprotective markers. These findings suggest that KD appears to promote brain resilience during aging, even in the presence of microbiota disruption.