法尼甾体X受体
肠道菌群
胆固醇7α羟化酶
胆汁酸
鹅去氧胆酸
内科学
回肠
微粒体甘油三酯转移蛋白
生物
内分泌学
胆酸
胆固醇
微生物学
生物化学
脂蛋白
医学
极低密度脂蛋白
核受体
转录因子
基因
作者
Xinjian Wan,Xin Ye,Qian Zhuang,Zhiya Dong,Xiaoxin Wang,Shuang Shen,Shan Wu,Min Ning,Jie Xia,Jingjing Wang
出处
期刊:Research Square - Research Square
日期:2020-12-04
标识
DOI:10.21203/rs.3.rs-120683/v1
摘要
Abstract Background Cholesterol gallstone (CGS) disease is characterized by an imbalance in bile acid (BA) metabolism and is closely associated with gut microbiota disorders. However, the role and mechanism by which probiotics targeting the gut microbiota attenuate CGS are still unknown. In this study, Lactobacillus reuteri CGMCC 17942 (LR) and L. plantarum CGMCC 14407 (LP) were individually administered to lithogenic diet (LD)-fed mice at a dosage of 10 9 CFU/day for 8 weeks. Results Both Lactobacillus strains significantly reduced LD-induced gallstones, hepatic steatosis, and hyperlipidemia. These strains modulated serum BA profiles, with significantly decreased conjugated primary BA taurine-β-muricholic acid (T-β-MCA), an FXR antagonist. At the molecular level, LR and LP increased Farnesoid X Receptor (FXR) expression in the liver but not in the ileum, increased the levels of ileum and liver fibroblast growth factor 15 (FGF15) and liver FGFR4, small heterodimer partner (SHP), and subsequently reduced cholesterol 7α-hydroxylase (CYP7A1) and cytochrome P450 family 7 subfamily B polypeptide 1 (CYP7B1) to inhibit BA synthesis in the liver. At the same time, the two strains enhanced BA transport by increasing the levels of multidrug-resistance-associated protein homologs (MRP) 3/4, multidrug-resistance-associated protein homologs (MRP) 3/4, hepatic multidrug resistance protein (MDR2) and bile salt export pump (BSEP) mRNA in the liver. In addition, both LR and LP reduced LD-associated gut microbiota dysbiosis. LR increased the relative abundance of Muribaculaceae , while LP increased that of Akkermansia. The changed gut microbiota was significantly negatively correlated with the grade and incidence of gallstones, hyperlipidemia, the level of T-β-MCA in serum, or the gene expression levels of Fxr in liver. Furthermore, the protective effects of the two strains were abolished by a global but not intestinal-specific FXR antagonist. Conclusions Taken together, our results suggested that Lactobacillus might relieve gallstones through FXR-dependent regulation of BA synthesis and transport.
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