Impact on Bile Acid Concentrations by Alveolar Echinococcosis and Treatment with Albendazole in Mice.

Cristina Gómez,Michael Weingartner,Britta Lundström-Stadelmann,Simon Stücheli,Fadi Jebbawi,Bruno Stieger,Bruno Gottstein,Guido Beldi,Alex Odermatt,Junhua Wang

doi:10.3390/metabo11070442

Abstract

Alveolar echinococcosis (AE) caused by Echinococcus multilocularis is a chronic, progressive liver disease widely distributed in the Northern Hemisphere. The main treatment options include surgical interventions and chemotherapy with benzimidazole albendazole (ABZ). To improve the current diagnosis and therapy of AE, further investigations into parasite–host interactions are needed. This study used liquid chromatography–tandem mass spectrometry (LC-MS/MS) to assess serum and liver tissue bile acid profiles in the i.p. chronic E. multilocularis-infected mouse model and evaluated the effects of the anthelmintic drug ABZ. Additionally, hepatic mRNA and protein expression of enzymes and transporters regulating bile acid concentrations were analyzed. AE significantly decreased unconjugated bile acids in serum and liver tissue. Taurine-conjugated bile salts were unchanged or increased in the serum and unchanged or decreased in the liver. Ratios of unconjugated to taurine-conjugated metabolites are proposed as useful serum markers of AE. The expression of the bile acid synthesis enzymes cytochrome P450 (CYP) 7A1 and aldo-keto reductase (AKR) 1D1 tended to decrease or were decreased in mice with AE, along with decreased expression of the bile acid transporters Na+/taurocholate cotransporting polypeptide (NTCP) and bile salt efflux pump (BSEP). Importantly, treatment with ABZ partially or completely reversed the effects induced by E. multilocularis infection. ABZ itself had no effect on the bile acid profiles and the expression of relevant enzymes and transporters. Further research is needed to uncover the exact mechanism of the AE-induced changes in bile acid homeostasis and to test whether serum bile acids and ratios thereof can serve as biomarkers of AE and for monitoring therapeutic efficacy.

Highlights

The natural mode of infection of intermediate hosts with E. multilocularis represents peroral uptake of infectious eggs, which includes the first phase of intrahepatic parasite development
The treatment efficacy of ABZ was demonstrated in the previous study by a significantly reduced parasite weight, the histopathology, and reduced liver tissue cytokine levels
Gene expression analyses of the present study indicated a decreased hepatic bile acid synthesis by lower CYP7A1 and AKR1D1 expression levels, along with decreased canalicular biliary secretion via bile salt efflux pump (BSEP), reduced bile acid and bile salt uptake from the portal circulation by Na+/taurocholate cotransporting polypeptide (NTCP) and OATP1B2, and reduced efflux to the general circulation by OSTα and MRP4 (Figure 5)

Summary

Introduction

Human alveolar echinococcosis (AE) caused by Echinococcus multilocularis is a severe liver disease with high morbidity and poor prognosis when handled inappropriately [1,2]. Adult stages of the tapeworm are mainly noted in the intestine of red and arctic foxes, domestic dogs and cats can act as definitive hosts [3,4]. The course of the infection is characterized by a long-term, primarily intrahepatic growth of the metacestode (larval stage) in the intermediate host, including small mammals such as mice [5]. Invasion of the bile ducts by E. multilocularis leads to cholangitis and portal hypertension, and the disease can progress to liver cirrhosis after a long latent, asymptomatic period [5,6]

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