Modulation of the Bile Acid Enterohepatic Cycle by Intestinal Microbiota Alleviates Alcohol Liver Disease.

Dragos Ciocan,Gabriel Perlemuter,Lydie Humbert,Aurore Desmons,Guido Kroemer,Sylvère Durand,Cindy Hugot,Françoise Mercier-Nomé,Séverine Domenichini,Kévin Hardonnière,Nicolas Trainel,Anne-Marie Cassard,Madeleine Spatz,Antonin Lamazière

doi:10.3390/cells11060968

Abstract

Reshaping the intestinal microbiota by the ingestion of fiber, such as pectin, improves alcohol-induced liver lesions in mice by modulating bacterial metabolites, including indoles, as well as bile acids (BAs). In this context, we aimed to elucidate how oral supplementation of pectin affects BA metabolism in alcohol-challenged mice receiving feces from patients with alcoholic hepatitis. Pectin reduced alcohol liver disease. This beneficial effect correlated with lower BA levels in the plasma and liver but higher levels in the caecum, suggesting that pectin stimulated BA excretion. Pectin modified the overall BA composition, favoring an augmentation in the proportion of hydrophilic forms in the liver, plasma, and gut. This effect was linked to an imbalance between hydrophobic and hydrophilic (less toxic) BAs in the gut. Pectin induced the enrichment of intestinal bacteria harboring genes that encode BA-metabolizing enzymes. The modulation of BA content by pectin inhibited farnesoid X receptor signaling in the ileum and the subsequent upregulation of Cyp7a1 in the liver. Despite an increase in BA synthesis, pectin reduced BA serum levels by promoting their intestinal excretion. In conclusion, pectin alleviates alcohol liver disease by modifying the BA cycle through effects on the intestinal microbiota and enhanced BA excretion.

Highlights

Alcohol liver disease (ALD) is the first cause of chronic liver disorders in Western countries [1]
ALD includes various histopathological characteristics, ranging from simple steatosis to steatohepatitis, fibrosis, and cirrhosis, but only 10 to 20% of patients evolve to advanced fibrosis and its complications [3]
Patients who develop life-threatening forms of ALD, such as severe alcoholic hepatitis, manifest specific changes in their bile acids (BAs) pool with a shift towards more hydrophobic and toxic species that may be responsible for specific changes in intestinal microbiota (IM) composition

Summary

Introduction

Alcohol liver disease (ALD) is the first cause of chronic liver disorders in Western countries [1]. Patients who develop life-threatening forms of ALD, such as severe alcoholic hepatitis (sAH), manifest specific changes in their BA pool with a shift towards more hydrophobic and toxic species that may be responsible for specific changes in IM composition. In these patients there is an increase in the plasma levels of total bile acids, plasma-conjugated cholic and chenodeoxycholic acid, ursodeoxycholic and lithocholic acid, whereas deoxycholic acid decreased [6,15]. It has been suggested that some BAs (taurochenodeoxycholic acid and tauroursodeoxycholic acid) can be related to disease severity [6,15]

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