Zhigang Liu

College of Food Science and Engineering, Northwest A&F University, No.22 Xinong Road, Yangling Shaanxi, 712100, China

Background and Objectives: In recent years, research on improving brain cognitive function through non-pharmacological interventions such as time-restricted feeding (TRF) has become a hot topic in the field of nutrition. The gut and brain interact through the nervous and circulatory systems. Our previous studies have shown that intermittent fasting can regulate the gut microbiota, increase short-chain fatty acids, tauroursodeoxycholic acid, and indole-3-propionic acid, and ameliorate insulin resistance-induced neuronal energy metabolism dysfunction. However, it is still unclear whether TRF can regulate cognitive dysfunction related to Alzheimer's disease (AD) via regulating the gut-brain axis.

Methods and Study Design: Based on AD transgenic animal models, we conducted a 3-month TRF intervention, utilizing behavioral tests, multi-omics analysis, microbiota removal, PET/CT, and inhibitors/lentiviral intervention to analyze the improvement of cognitive dysfunction in AD and the gut-brain axis mechanism.

Results: The current study found that TRF improved cognitive function in AD mice and reduced the excessive deposition of Aβ. TRF intervention reshaped the gut microbiota of AD mice and increased propionic acid levels in feces. Further validation revealed that propionic acid and Bifidobacterium pseudolongum (a propionic acid-producing bacterium) supplementation yielded similar results to TRF in improving AD cognitive function. TRF intervention restored brain propionic acid metabolism and inhibited neuroinflammation. Concurrently, our additional research also demonstrates the critical mediating role of the tryptophan metabolite indole-3-propionic acid in the improvement of AD cognitive function through intermittent fasting.

Conclusion: Our research revealed that time-restricted feeding effectively improves AD-related cognitive dysfunction, partly through regulating the expression of neuroprotective gut microbial metabolites. This study provides new theoretical foundations for brain health nutrition intervention strategies through regulating dietary rhythms or intervening in gut microbiota homeostasis.