Cholestasis induced by bile duct ligation promotes changes in the intestinal microbiome in mice

Raul Cabrera-Rubio,Paul D Cotter,Naiara Beraza,Angela M Patterson

doi:10.1038/s41598-019-48784-z

Abstract

Increasing evidence point to the relevance of intestinal disfunction and changes in the microbiome composition during chronic liver disease. More specifically, recent studies have highlighted that cholestatic diseases associate with a reduction in the microbiome diversity in patients. Still, the dynamics of the changes in the microbiome composition observed, as well as their implication in contributing to the pathogenesis of this disease remain largely undefined. Hence, experimental mouse models resembling the human pathogenesis are crucial to move forward our understanding on the mechanisms underpinning cholestatic disease and to enable the development of effective therapeutics. Our results show that the bile duct ligation (BDL) experimental model of cholestasis leads to rapid and significant changes in the microbiome diversity, with more than 100 OTUs being significantly different in faecal samples obtained from WT mice at 3 days and 7 days after BDL when compared to control animals. Changes in the microbial composition in mice after BDL included the enrichment of Akkermansia, Prevotella, Bacteroides and unclassified Ruminococcaceae in parallel with a drastic reduction of the presence of Faecalibacterium prausnitzii. In conclusion, our results support that bile duct ligation induces changes in the microbiome that partly resemble the gut microbial changes observed during human cholestatic disease.

Highlights

Our intestine is home to trillions of microorganisms, including bacteria, archaea, fungi and virus, which can be regarded as a superorgan referred to as the gut microbiota, while the gut microbiome refers to the microbial genome
The ‘leaky gut’ hypothesis proposes that intestinal bacteria, endotoxin or other bacterial products translocate from the permeable gut into the liver via the porta circulation, triggering hepatic inflammation and fibrosis further contributing to the progression of chronic liver disease[5,7]
Our in-depth 16S rRNA-based analysis shows that bile duct ligation (BDL) induces significant changes in the intestinal microbiome composition of mice, characterised by a reduction in diversity at early stages and changes in the abundance of particular bacteria, partially resembling the observations described during human cholestasis

Summary

Introduction

Our intestine is home to trillions of microorganisms, including bacteria, archaea, fungi and virus, which can be regarded as a superorgan referred to as the gut microbiota, while the gut microbiome refers to the microbial genome. Based on the complexity of the multiple molecular events undergoing during cholestasis, involving interactions between different liver cell types and the gut-microbiome-liver axis, the current consensus is that there is not a unique animal model fully recapitulating human cholestatic disease[20]. While concurring with this conclusion, we here demonstrate that bile duct ligation (BDL) is a plausible model to investigate the functional relevance of the microbiome in the pathogenesis of cholestasis. Our in-depth 16S rRNA-based analysis shows that BDL induces significant changes in the intestinal microbiome composition of mice, characterised by a reduction in diversity at early stages and changes in the abundance of particular bacteria, partially resembling the observations described during human cholestasis

Methods

Results

Conclusion