Timing Of Calorie Restriction In Mice Impacts Host Metabolic Phenotypes With Correlative Changes In Gut Microbiota

Erratic daily eating patterns are prevalent in modern society,with people eating more frequently throughout the day and with a bias toward late-night eating.Accumulating evidences show that the timing of food access strongly impacts the health outcomes.Calorie restriction(CR)has been shown to extend lifespan and improve health in various animal models.However,whether restriction of food to daytime in comparison to nighttime,coupled with restricted calorie intake,can influence gut microbiota,metabolism,and overall health requires further investigation.In this work,SPF C57BL/6J male mice were placed on a light-fed or dark-fed CR protocol to survey the effects of shifting feeding time on gut microbiota and metabolic phenotype.Since many people who diet to lose weight find it logistically difficult to implement CR over the lifetime,and undergo excessive weight regain cycles.We also explore the lasting effects of these two types of CR by switching the mice to ad libitum feeding schedule after the 4-week CR period.Results show that light-fed CR mice display physiological changes such as muscle loss,concomitant with changes in the gut microbiota structure and composition.After switching to ad libitum access to food,light-fed mice had a period of food-craving behavior and short-lived physiological changes,while dark-fed mice display lasting changes,including fat accumulation,glucose metabolism,intestinal barrier function,and the reduction of systemic inflammatory marker.Moreover,the gut microbiota was modulated by when the food was consumed,and the most abundant Lactobacillus OTU promoted by CR was enhanced in dark-fed mice.After switching to ad libitum feeding,the gut microbiota of dark-fed mice returned to the state resembling that of mice fed normal chow ad libitum,but that of light-fed mice was still significantly different from the other two groups.Together these data indicate that for CR,restricting food consumption to the active phase brought better metabolic phenotype associated with potentially beneficial structural shifts in the gut microbiota.Timing of food access should be taken into careful consideration in CR regimen.In light of the fact that humans naturally spend the light phase in the active/feeding state and the dark phase in the resting/fasting state,avoiding time of eating close to or during the rest period when people are on a diet might generate better metabolic outcomes.Our work strengthens the evidence for using“when to eat” as an intervention to improve health during calorie restriction.