Intermittent Fasting Alleviates Diabetes-induced Cognitive Decline via Gut Microbiota-metabolites-brain Axis (OR32-04-19)

Cognitive decline is one of severe type 2 diabetes complications. Intermittent fasting (IF) is a promising dietary intervention for T2D risk reduction, but its protective effect and mechanism on diabetic cognitive dysfunction remain elusive. Gut microbiota plays a vital role interphasing diet and host physiology and pathology and highly affected by the dietary composition and patterns. It has been reported that the microbiota homeostasis is essential for maintenance of gut health and for modulating cognitive function. We hypothesized that gut microbiota might play a pivotal role in mediating protective effects of IF on diabetes-induced cognitive decline. After a 28-day IF regimen treatment, cognitive behavioral tests and brain insulin signaling were assessed on db/db mice. The microbiota-metabolites-brain axis alterations were detected by multiple-omics analysis (transciptomics, 16S rRNA sequencing and metabolomics). A intergrade multi-omics analysis was performed to analyze the correlation among gut microbiota, plasma metabolites, and hippocampal gene expression. Here we found that a 28-day Intermittent fasting (IF) regimen improved cognitive deficits in db/db mice via a microbiota-metabolites-brain axis assessed by behavioral tests and multiple-omics analysis: IF activated AMPK/PGC1α signaling, enhanced mitochondrial biogenesis in hippocampus and elevated genes enriched in hippocampal metabolic function. Moreover, IF re-structured gut microbiota and improved plasma microbial metabolites in relation to diabetes and cognitive function, e.g., serotonin, 3-Indolepropionic acid, and bile acids. Integration of multi-omics data demonstrated strong links between IF-related genes, gut microbiome and metabolites. Furthermore, removal of gut microbiota with antibiotics partly abolished the observed benefits of IF on cognition and hippocampal metabolic function. Taken together, the present study suggests a critical role of gut microbiota in connecting peripheral metabolism with brain function, which could lead to novel interventions against metabolism-implicated neurodegenerative pathophysiologies. This work was financially supported by the National Key Research and Development Program of China, National Natural Science Foundation of China.