Lactobacillus rhamnosus GG (LGG) treatment significantly reduces hepatic bile acids and liver injury in bile duct ligation mice.
LGG treatment attenuates liver inflammation, injury, and fibrosis in bile duct ligation mice.
Hepatic levels of taurine-β-muricholic acid were significantly higher in untreated bile duct ligation mice compared to those treated with LGG.
Chenodeoxycholic acid levels were decreased in untreated bile duct ligation mice but normalized with LGG treatment.
LGG treatment increased the expression of fibroblast growth factor 15, which is associated with reduced bile acid synthesis.
Alterations in gut microbiota due to LGG treatment are linked to increased bile acid deconjugation and enhanced bile acid excretion.
Simplified
BACKGROUND AND AIMS: is characterized by gut dysbiosis and excessive toxic hepatic bile acids (BAs). Modification of gut microbiota and repression of BA synthesis are potential strategies for the treatment of cholestatic liver disease. The purpose of this study was to examine the effects and to understand the mechanisms of the probiotic Lactobacillus rhamnosus GG (LGG) on hepatic BA synthesis, liver injury, and fibrosis in bile duct ligation (BDL) and multidrug resistance protein 2 knockout (Mdr2) mice. -/-
APPROACH AND RESULTS: Global and intestine-specific farnesoid X receptor (FXR) inhibitors were used to dissect the role of FXR. LGG treatment significantly attenuated liver inflammation, injury, and fibrosis with a significant reduction of hepatic BAs in BDL mice. Hepatic concentration of taurine-β-muricholic acid (T-βMCA), an FXR antagonist, was markedly increased in BDL mice and reduced in LGG-treated mice, while chenodeoxycholic acid, an FXR agonist, was decreased in BDL mice and normalized in LGG-treated mice. LGG treatment significantly increased the expression of serum and ileum fibroblast growth factor 15 (FGF-15) and subsequently reduced hepatic cholesterol 7α-hydroxylase and BA synthesis in BDL and Mdr2mice. At the molecular level, these changes were reversed by global and intestine-specific FXR inhibitors in BDL mice. In addition, LGG treatment altered gut microbiota, which was associated with increased BA deconjugation and increased fecal and urine BA excretion in both BDL and Mdr2mice. In vitro studies showed that LGG suppressed the inhibitory effect of T-βMCA on FXR and FGF-19 expression in Caco-2 cells. -/--/-
CONCLUSION: LGG supplementation decreases hepatic BA by increasing intestinal FXR-FGF-15 signaling pathway-mediated suppression of BA de novo synthesis and enhances BA excretion, which prevents excessive BA-induced liver injury and fibrosis in mice.
Key numbers
significantly reduced
Decrease in liver fibrosis markers
Compared to BDL mice without LGG treatment.
significantly reduced
Reduction in hepatic CYP7A1 expression
Observed in BDL-operated mice treated with LGG.
significantly increased
Increase in FGF15 levels
In BDL mice following LGG treatment.
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