Study On The Lipid-lowering Effect And Mechanism Of Noni Fruit Polysaccharide Based On Bile Acid Enterohepatic Circulation

Objective: Obesity is a serious health hazard worldwide and is a major risk factor for hyperlipidemia,non-alcoholic fatty liver disease(NAFLD),and cardiovascular disease(CVD).Therefore,prevention and treatment of overweight,obesity,and related complications have become increasingly important.Noni fruit polysaccharide(NP)has antioxidant,anti-inflammatory and other effects.Our previous studies have shown that NP has lipid-lowering and weight-loss effects,but its mechanism is not clear.Bile acids are important signaling molecules that regulate metabolism and are closely associated with obesity.Therefore,this study explored the lipid-lowering effect and mechanism of NP based on bile acid metabolism.Methods: First,the binding of NP to bile acid salts was studied by simulating the gastrointestinal tract in vitro.For further in vivo experiments,C57BL/6 mice were randomly divided into normal control group,high-fat diet model group,and NP low,medium and high dose groups(high-fat diet + 100 mg/(kg.bw),200 mg/(kg.bw)and 400mg/(kg.bw)NP)and fed for 12 weeks.The body weight,epididymal fat index,liver index,liver pathology,serum TC,TG,LDL-C,HDL-C and TBA levels,liver tissue and feces were measured and analyzed.Expression of proteins related to bile acid metabolism was detected by WB,bile acid profiles in mouse feces were analyzed by LC-MS assay,and the diversity and composition of mouse gut microbiota were analyzed by 16 S r RNA sequencing.Results: 1.In vitro binding experiments showed that the binding rate of NP to sodium taurocholate was 46.67% and the binding rate to glycocholic acid was 44.33%.2.Compared with the model group,NP inhibited rapid body weight gain,reduced serum TC,TG and TBA levels and liver TC and TG contents in mice on high-fat diet.Furthermore,treatment with NP reduced t the expression of hepatic inflammatory factors TNF-α,IL-6 and NF-ΚB and downregulated the expression of CYP7A1 protein.In addition,NP promoted the excretion of fecal TC,TG and TBA in mice on a high-fat diet。3.NP significantly activated the protein expressions of FXR and FGF15 in the liver and intestine compared with the model group.The intervention of NP affected the composition of the fecal bile acid profile,in particular by increasing the excretion of conjugated bile acids(Tα-MCA and Tβ-MCA).In addition,NP was effective in improving the diversity and composition of the gut microbiota in mice fed a high-fat diet,such as increasing the relative abundance of Allobaculum,Lactobacillus,Anaerotruncus and Bilophila,and decreasing the relative abundance of Coprococcus,Odoribacter,Dehalobacterium and Alistipes.Conclusion: This study demonstrates that NP may promote fecal excretion by binding to bile acids and reducing their reabsorption,especially the significantly increased levels of Tα-MCA and Tβ-MCA.NP activates the intestinal FXR-FGF15 pathway and hepatic FXR expression to regulate lipid metabolism.Additionally,it may also promote the growth of bile salt hydrolase(BSH)producing Lactobacillus and isobacillus in the intestine of mice on a high-fat diet,allowing more free bile acids in the body to promote secondary bile acid synthesis,which in turn improves lipid metabolism.