Commun Biol. 2025 Dec 7. doi: 10.1038/s42003-025-09171-9. Online ahead of print.

ABSTRACT

The systemic mechanisms underlying the benefits of ketogenic interventions on cognition in Alzheimer’s disease (AD) are understudied. Interventions involving a carbohydrate-free high-fat ketogenic diet (KD) or dietary supplementation with medium-chain triglycerides (MCT) both improve cognition in AD mouse models, yet with opposing effects on circulating ketones levels, peripheral insulin sensitivity and inflammation. Since the gut microbiome regulates systemic metabolism and inflammation and is altered by aging and disease, we investigated how it is affected in mice subjected to MCT and KD. At early stages of pathology, AD mice exhibited substantially reduced richness and distinct composition of gut microbiome species. Administration of MCT or KD for 1-month increased microbiome diversity, restoring the levels of more than 50% of the bacteria altered in AD mice and inducing novel alterations. Both diets increased levels of short-chain fatty acid-producing bacteria, such as Lachnospiraceae, which directly correlated with improved hippocampal dendritic spine density. Interestingly, longer term administration of KD increased the obesity-associated Firmicutes/Bacteroidota ratio and bodyweight in AD but not WT mice, suggesting that AD-associated metabolic defects should be considered when designing such intervention. We conclude that MCT and KD may influence AD central and peripheral defects in part via modulation of the gut microbiome.

PMID:41354833 | DOI:10.1038/s42003-025-09171-9

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