Short-Chain Fatty Acids Improve Hippocampal Atrophy, Ventricular Dilatation and Cognitive Function Decline in Aged Mice

Many countries are becoming aged or super-aged societies. This demographic shift causes substantial social, economic, and personal costs directly and indirectly attributable to cognitive decline. Recent studies have shown that dietary fiber can slow down memory decline, with short-chain fatty acids being the primary metabolites produced by gut microbiota from the fermentation of dietary fiber. Despite this, there are limited studies investigating the effect of SCFAs on age-related cognitive function and morphological changes of the brain. In this study, we used B6C3F1 male mice at the age of 3 months and treated them with water, low dose, and high dose SCFAs for 9 months. We assessed their short- and long-term cognitive functions using the Novel Object Recognition test, Morris Water Maze, and Rotarod test. Their brain structure was assessed by 7 Tetra Magnetic Resonance Imaging (7TMRI) and gut microbiota analyzed by 16S rRNA sequencing. Our results show that both short-term and long-term SCFA treatment significantly improve cognitive deficits in the Novel Objective Recognition test and Morris Water Maze tests. Additionally, the 7T MRI results show that SCFAs mitigated hippocampal atrophy compared to the control group. These improvements were accompanied by alteration of gut microbiota composition. We also found that, after treatment, the beneficial gut microbiota Alloprevotella was positively correlated with hippocampal volume. Therefore, we propose that SCFAs may be a promising therapeutic strategy to counteract age-related cognitive decline.