The Study On The Mechanism Of Gut Microbiota Dysbiosis Promoting Cholecystolithiasis And Non-alcoholic Fatty Liver Disease After Cholecystectomy

Gut microbiota is closely linked to people’s metabolic health and disease risk.More and more attention has been paid to the correlation between gut microbiota dysbiosis and hepatobiliary diseases.The first part of this study explored the correlation between gut microbiota dysbiosis and the development of nonalcoholic fatty liver disease（NAFLD）in mice after cholecystectomy.There is increasing evidence that cholecystectomy is an independent risk factor for NAFLD.However,the underlying mechanisms leading to liver lipid deposition after cholecystectomy remain unclear.In this research,after cholecystectomy or sham operation,8-week-old male C57BL/6J mice were fed a high-fat diet for 84 days.We found that cholecystectomy resulted in 1)aggravated metabolic disorders,increased liver/body weight ratio and liver triglyceride content,significant glucose intolerance;2)aggravated hepatic steatosis and fibrosis,causing severe steatohepatitis;3)changes in the gene expression related to liver inflammation,bile acid metabolism and intestinal epithelial tight junction;4)the composition of gut microbiota changed significantly.Our results suggest that cholecystectomy alters the distribution of gut microbiota in mice,which may contribute to the development of NAFLD in high-fat diet fed mice.The results of this study provide a new theoretical and experimental basis for correctly understanding the adverse effects of gut microbiota dysbiosis after cholecystectomy,and how to protect gallbladder function,prevent and treat NAFLD.The second part of this study explored the correlation between gut microbiota dysbiosis and gallstone disease.Cholesterol gallstones is a common disease all over the world.Cholesterol supersaturation in gallbladder bile is a prerequisite for cholelithiasis,but the mechanism is not completely clear.In this study,we found that:1)Desulfovibrionales abundance enriched in the gut microbiota from patients with cholesterol gallstones and in C57BL/6J gallstone-susceptible mice;2)gallstone formation in mice could be promoted by fecal microbiota transplantation（FMT）from patients with cholesterol gallstones,co-housing with C57BL/6J gallstone-susceptible mice,and inoculation specific Desulfovibrionales species;3)the enrichment of Desulfovibrionales increased the secondary bile acids generated by gut microbiota,resulting in an increase of bile acids hydrophobicity,which is conducive to intestinal cholesterol absorption;4)Desulfovibrionales could induced hepatic expression of cholesterol transporters Abcg5/g8 to promote biliary secretion of cholesterol into bile.5)H₂S increased in the mice carrying Desulfovibrionales which would induce hepatic FXR and inhibite CYP7A1 expression and resulted in inhibition of bile acid synthesis from cholesterol.Our study explored the pathogenesis of gallstone disease from the perspective of gut microbiota,proved that carrying Desulfovibrionales promoted the formation of gallstones,and explained the regulatory role of gut microbiota on cholesterol absorption,secretion,and transformation from the perspective of bile acid and cholesterol metabolism in the enterohepatic axis.