日间限时进食诱导昼夜节律去同步化和代谢紊乱伴胆汁酸谱和肠道菌群改变

Abstract

Fasting/feeding cycles regulate clock-lipid-bile acid (BA) metabolic homeostasis, and gut microbiota also participates in connecting circadian rhythms with BA metabolism. To investigate the cyclical nature of microbial-metabolism-host interactions, sixty male C57BL/6 mice were randomized into three feeding regimens with a chow diet: 24 h ad libitum (AC), 12 h nighttime feeding (NC) or 12 h daytime feeding (DC). Five weeks later, the mice were sacrificed at six-hour intervals over 24 hours. Daytime feeding abolished hepatic rhythmic expressions of Per1, Cry1/2 and Rev-erbα or changed the acrophase of Clock, Bmal1 and Per2 , also the rhythmic expression of genes Hsl, Fas, Acc, Srebp-1c in lipid homeostasis and Cyp7a1, Cyp7b1, Cyp8b1, Lrh-1 and Shp in bile acid metabolism compared with their ad libitum and dark-fed companions. Furthermore, daytime feeding upregulated the levels of fecal primary BA, secondary BA and unconjugated BA at ZT0 and decreased their levels at ZT12. Meanwhile, daytime feeding altered the diversity of gut microbiota and microbiota compositions, with obviously higher abundance of Firmicutes and F/B ratio, and significantly lower abundance of Verrucomicrobia, as well as altered fluctuations of Akkermansia, Lactobacillus and Parabacteroides . In conclusion, shifting food intake to the rest phase caused a desynchronization in the liver between circadian rhythm and metabolism, as well as abnormal circadian variations in fecal BA profiles and gut microbiota.