Intermittent fasting (DI) can mitigate cognitive impairment in Alzheimer’s disease (AD) probably through modulation of the gut-metabolite-brain microbiota axis.
- A 16-week DI regimen significantly improved spatial memory and cognitive function in AD transgenic mice; this improvement was accompanied by reduced Aβ accumulation and suppression of neuroinflammation. DI reshaped the microbiota and positively altered microbial metabolites related to cognitive function. Multi-omics analysis demonstrated a strong connection between DI-induced changes in hippocampal gene expression, the composition of gut microbes, and serum metabolites useful for cognitive function.
- DI alters the intestinal microbial composition with significant enrichment of probiotics such as Lactobacillus. Changes in the composition of the gut microbiota affect metabolic activities and metabolite production. Metabolomic profile analysis of the cecal contents revealed that DI leads to reduced metabolism of carbohydrates (e.g., glucose) and increased abundance of amino acids (e.g., sarcosine and dimethylglycine). It is noteworthy that administration of sarcosine or dimethylglycine mimics the protective effects of DI in transgenic mice with AD, including amelioration of cognitive decline, amyloid-β (Aβ) load, and glial hyperactivation.
- Removal of gut microbes with antibiotics abolished the neuroprotective effects of DI.
These results thus demonstrate that an IF regimen is a potential approach to prevent AD progression, at least through the gut-microbiota-metabolite-brain axis, and is a novel AD therapeutic pathway.