The Role And Mechanism Of Gut Microbiota-bile Acid Metabolism In Rebound Weight Gain After Calorie Restriction

Calorie-restricted diet is one of the most used weight-loss method.However,it turns out that it is difficult to maintain the state of weight loss after returning to the original eating habits,and even more obvious weight gain after calorie restriction.But the mechanism has not been elucidated.The components of the diet can regulate the composition of microbes in the gut,which in turn affects the digestion and absorption of nutrients.Bile acids,which are involved in the metabolism of intestinal flora,are important signaling molecules that regulate the body’s metabolism,and play an important role in the body’s glucose and lipid metabolism and energy metabolism.Therefore,the metabolic role of gut microbiota-bile acids may be an important breakthrough to study the mechanism of weight rebound after calorie restriction.Therefore,this study designed the mice experiments to explore the difference in weight rebound after calorie restriction: high-fat diet,chow diet,or 40% calorie restriction for 12 weeks,then switched to the high-fat diet for 8 weeks.From this,we found a rapid weight rebound in the calorierestricted group,as well as impaired glucose and lipid metabolic homeostasis and reduced energy expenditure after weight regain.The mice model confirmed that after different basal diets,the high-fat diet-induced weight gain and metabolic disturbance in mice were different,and mice with calorie-restricted diet intervention were more prone to weight rebound.Based on this mice model,the study examined the differences in gut microbiota and bile acid profiles after three dietary interventions to explore whether gut microbiota-bile acids were the underlying cause of weight regain.The metagenomic sequencing was used to detect and analyze the gut microbiota of mice in high-fat,chow,and 40% calorie-restricted diets.Both calorie restriction and high-fat diets reshaped gut microbial composition compared with normal diets.The relative abundances of some species were similar in the calorie restriction group and the high-fat diet group,which may be a key factor of weight rebound in the recovery of high-fat diet.In metabolic functional pathway analysis of intestinal bacteria,secondary bile acids metabolism pathways were found to be significantly decreased in both caloric restriction and high-fat diets.By using ultra-performance liquid chromatography-triple quadrupole mass spectrometry(UPLC-TQMS),quantitative analysis of bile acid profiles was performed.In both caloric restriction and high-fat diets,the bile acid composition was significantly changed and the proportion of non-12α-hydroxylated bile acids(there is no hydroxyl group at the 12α position in the structure,hereinafter referred to as non-12α-OH)was decreased.In order to find the most critical information on the interaction with bile acids from a large number of differential bacteria,we used the cross-omics correlation analysis method of microbiome and metabolome data developed and established by ourselves.We found that Parabacteroides distasonis(P.distasonis)and non-12α-OH bile acid ursodeoxycholic acid(UDCA)had the strongest correlation.In vitro experiments confirmed that P.distasonis has the function of metabolizing UDCA,and has the characteristics of preferentially metabolizing non-12α-OH bile acids.Furthermore,in the mice model that restores energy intake after caloric restriction,a sustained reduction in P.distasonis and the ratio of UDCA and lithocholic acid(LCA)to total bile acid concentrations were found.This bile acid profile leading to downregulation of the receptor Takeda G proteincoupled receptor 5(TGR5)in the ileum and brown fat,decreased expression of uncoupling protein-1(UCP1)in brown fat,and decreased energy expenditure levels in the weight regain.Based on the above results,the study targeted gut bacteria and bile acids during resumption of a high-fat diet after calorie restriction in the mouse model,P.distasonis and UDCA were continued to be used to intervene in weight-rebound mice to explore their therapeutic effects.We found that following P.distasonis or UDCA intervention,the degree of weight regain in mice was significantly reduced,accompanied by activation of brown fat UCP1 pathway and increased energy expenditure.P.distasonis could reshape the gut microbiota and bile acid distribution in weightrebound mice and adjusted the ratio of Firmicutes to Bacteroidetes and the proportions of unconjugated non-12α-OH bile acids of UDCA and LCA.To demonstrate the critical role of UCP1 in therapeutic mediation,further experimental studies were conducted using uncoupling-protein 1 knockout(UCP1-KO)mice.We found that the ameliorating effects of P.distasonis and UDCA on weight regain were not observed in UCP1-KO mice.These results confirmed that P.distasonis or the non-12α-OH bile acid UDCA enhances energy expenditure by activating the UCP1 thermogenic pathway,thereby alleviating weight rebound after caloric restriction.This study explored the impact of the crosstalk between gut microbes and bile acids on weight rebound after calorie restriction and energy expenditure.P.distasonis and its metabolite UDCA could effectively alleviate post-calorie restriction weight rebound by mediating UCP1 activation.These results suggested that P.distasonis has potential as a probiotic,the supplementation of P.distasonis may be an effective strategy to prevent weight regain after weight loss.