Effect Of Intermittent Fasting On Metabolic Health And Gut Microbiota Of Normal Chow-fed And High Fat Diet-fed Mice

The gut microbiota plays a critical role in the health of the host.The composition of diet and eating pattern has great impacts on the structure of gut microbiota.Intermittent fasting?IF?,a form of dietary intervention,has recently become more and more popular in the population.IF can exert health-improving effect that is similar to calorie restriction?CR?.In addition,there are many similarities in physiological changes caused by IF and CR.Several studies have found that both CR and IF directly induced dramatic changes in gut microbiota,and the modulated gut microbiota at least partially mediated their health-promoting effects.However,whether the dietary composition influents the effect of IF and whether IF-modulated gut microbiota and CR-modulated gut microbiota have any similarities are unknown.So,further researchs are needed to make IF a successful and reliable dietary intervention pattern.First,SPF C57BL/6J male mice fed a normal chow diet?NC?were employed to reveal the dynamic responses of the gut microbiota to IF.Mice were assigned into four groups:the first group received normal chow ad libitum?NC+AL group?,the second was fed 70%of NC+AL daily intake?NC+CR group?,the third was subjected to the IF regimen that was a 2-day?Day1 and Day2?fasting followed by a 5-day?Day3–Day7?ad libitum weekly?NC+IF group?,the forth was subjected to the IF^Ctrltrl regimen that was a2-day?Day1 and Day2?fasting followed by a 5-day?Day3–Day7?daily feeding 100%of the NC+AL daily intake?normal amounts of food?weekly to prevent overeating on refeeding days(NC+IF^Ctrl group).The intervention lasted for 11 weeks to explore the effects of these three dietary interventions on metabolic health and gut microbiota.Here the results showed that both NC+CR and NC+IF^Ctrl significantly improved the metabolic health in mice,including decreased weight loss and body fat mass,improved glucose metabolism,decreased serum levels of cholesterol whereas NC+IF had no such beneficial effects.The gut microbiota of the NC+CR group was relatively stable,which was dominated by OTU2 belonging to Lactobacillus;the gut microbiota of NC+IF^Ctrltrl and NC+IF groups changed periodically with the fasting-feeding cycle every week,and their gut microbiota at Day 2 and 3 was similar,but at Day7?0?,the gut microbiota of the NC+IF^Ctrl group was the same as NC+CR group,which was dominated by OTU2belonging to Lactobacillus,while the NC+IF group has the same gut microbiota as the NC+AL group.Interestingly,the fact that the gut microbiota of the NC+IF^Ctrl group at Day7?0?was the same as that of NC+CR group was just in parallel with their similar effects on health improvement.And the similarity of gut microbiota between the NC+IF group at Day7?0?and the NC+AL group was just in parallel with the rare health-improving effect of NC+IF.Moreover,OTU2 enriched by NC+CR and NC+IF^Ctrl in this study was completely consistent with the 16S rRNA V3-V4 sequence of Lactobacillus murinus?L.murinus?CR147 strain isolated from the gut of CR mice in our previous study.L.murinus CR147 could increase intestinal barrier function and had anti-inflammatory and health-promoting effects.It is suggested that the dominant Lactobacillus in the gut microbiota shaped by NC+CR and NC+IF^Ctrl may contribute to their host health benefits.Then,we further explored the response of the gut microbiota of high fat diet?HF?-fed mice to these three dietary regimens.SPF C57BL/6J male mice fed a high fat diet were assigned into four groups:the first group received high fat diet ad libitum?HF+AL group?,the second was fed 70%of the HF+AL daily intake?HF+CR group?,the third was subjected to the IF regimen?HF+IF group?,the forth was subjected to the IF^Ctrl regimen(HF+IF^Ctrl group).The intervention also lasted for 11 weeks to explore the effects of these three dietary interventions on metabolic health and gut microbiota.The results showed that HF+CR,HF+IF and HF+IF^Ctrl all could significantly alleviated obesity,fat accumulation,insulin resistance induced by HF and improved glucose-insulin homeostasis.The gut microbiota of HF+CR,HF+IF and HF+IF^Ctrltrl groups at Day7?0?was very similar and OTU2 belonging to Lactobacillus was significantly enriched,which were significantly different from the HF+AL group.The gut microbiota of HF+IF^Ctrl and HF+IF groups also changed periodically with the fasting-feeding cycle.The gut microbiota modulated by three dietary regimens may partly explain their ability to alleviate obesity and related metabolic disorders induced by HF.We next explored the effect of L.murinus CR147 on intestinal inflammation and its impact to host gut microbiota using murine dextran sulphate sodium?DSS?-induced chronic colitis model to further investigate its ability to resist inflammation and improve health.In our study,inoculating CR147 strain to DSS-treated mice could accelerate the remission of disease activity index and fecal Lipocalin-2,a sensitive biomarker for intestinal inflammation,and significantly increase?diversity of the gut microbiota.CR147 strain significantly altered the overall structure of gut microbiota.These findings indicated that L.murinus CR147 can accelerate the recovery of DSS-induced chronic colitis in mice and may exert anti-inflammatory effects by modulating the gut microbiota.Taken together,this study found that both CR and IF^Ctrl could improve the metabolic health of mice no matter mice were fed NC or HF,while IF only worked when mice were fed HF.IF and IF^Ctrl caused the gut microbiota to periodically change with the fasting-feeding cycle,but the gut microbiota of IF^Ctrl at Day7?0?were same as that of CR group which enriched OTU2 belonging to Lactobacillus,while IF intervention enriched OTU2 only in high-fat diet mice.Given that OTU2 is identical to the 16S rRNA V3-V4 sequence of the L.murinus CR147 strain with health-promoting effects,the predominant Lactobacillus may be one of the key members of the microbiota that contributed to the beneficial effects of NC+CR,NC+IF^Ctrl,HF+CR,HF+IF and HF+IF^Ctrl.This study has reference significance for human to promote health through dietary intervention,suggesting that the effect of certain dietary intervention may be different under different dietary structure and the gut microbiota modulated by effective dietary pattern may play an important role in improving metabolism.