Probiotic Lactobacillus rhamnosus GG Prevents Liver Fibrosis Through Inhibiting Hepatic Bile Acid Synthesis and Enhancing Bile Acid Excretion in Mice.

Abstract

BACKGROUND AND AIMS:

Cholestatic liver disease 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 Mdr2-/- mice. 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 Mdr2-/- mice. 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.

• Authors: Yunhuan Liu, Kefei Chen, Fengyuan Li, Zelin Gu, Qi Liu, Liqing He, Tuo Shao, Qing Song, Fenxia Zhu, Lihua Zhang, Mengwei Jiang, Yun Zhou, Shirish Barve, Xiang Zhang, Craig J McClain, Wenke Feng
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 71 Issue 6 Pg. 2050-2066 (06 2020) ISSN: 1527-3350 [Electronic] United States
• PMID: 31571251 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2019 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B
• Bile Acids and Salts
• Cholic Acids
• P-glycoprotein 2
• Receptors, Cytoplasmic and Nuclear
• fibroblast growth factor 15, mouse
• farnesoid X-activated receptor
• Chenodeoxycholic Acid
• muricholic acid
• Fibroblast Growth Factors

Topics

• ATP Binding Cassette Transporter, Subfamily B (genetics)
• Animals
• Bile Acids and Salts (biosynthesis, metabolism)
• Chenodeoxycholic Acid (pharmacology)
• Cholestasis (complications, metabolism, therapy)
• Cholic Acids (pharmacology)
• Fibroblast Growth Factors (metabolism)
• Gastrointestinal Microbiome (drug effects)
• Humans
• Intestines (microbiology)
• Lacticaseibacillus rhamnosus (metabolism)
• Liver Cirrhosis (etiology, prevention & control)
• Mice
• Mice, Knockout
• Probiotics (pharmacology)
• Receptors, Cytoplasmic and Nuclear (agonists, antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)