Intermittent fasting protects against Alzheimer’s disease in mice by altering metabolism through remodeling of the gut microbiota

Alzheimer's disease (AD) is the most common form of dementia without effective clinical treatment. Here, we show that intermittent fasting (IF) improves cognitive functions and AD-like pathology in a transgenic AD mouse model (5XFAD). IF alters gut microbial composition with a significant enrichment in probiotics such as Lactobacillus. The changes in the composition of the gut microbiota affect metabolic activities and metabolite production. Metabolomic profiling analysis of cecal contents revealed IF leads to a decreased carbohydrate metabolism (for example, glucose) and an increased abundance in amino acids (for example, sarcosine and dimethylglycine). Interestingly, we found that the administration of IF-elevated sarcosine or dimethylglycine mimics the protective effects of IF in 5XFAD mice, including the amelioration of cognitive decline, amyloid-β (Aβ) burden and glial overactivation. Our findings thus demonstrate an IF regimen is a potential approach to prevent AD progression, at least through the gut-microbiota-metabolites-brain axis, and constitutes an innovative AD therapeutic avenue.