Combination treatment with n-3 polyunsaturated fatty acids and ursodeoxycholic acid dissolves cholesterol gallstones in mice

Sung Ill Jang,Jieun Oh,Su Yeon Lee,Ga Young Hong,Kwang Pyo Kim,Joon Mee Kim,Younhee Ko,Dong Ki Lee,Sungsoon Fang,Ilkoo Noh,Hyoseon Kim

doi:10.1038/s41598-019-49095-z

Abstract

The increasing prevalence of cholesterol gallstone disease places an economic burden on the healthcare system. To identify novel therapeutics, we assessed the effects of n-3 polyunsaturated fatty acids (PUFA) in combination with UDCA in a mouse model of cholesterol gallstones. Gallstone dissolution, gallbladder wall thickness, mucin gene expression in the gallbladder, and levels of phospholipids, cholesterol, and bile acids in bile and serum were analysed. RNA was extracted from the liver for mRNA sequencing and gene expression profiling. Combination treatment resulted in greater gallstone dissolution compared with the control group, and PUFA and combination treatments reduced the thickness of the gallbladder wall. Expression levels of mucin genes were significantly lower in the UDCA, PUFA, and combination groups. Transcriptome analyses revealed that combination treatment modulated hepatic lipid metabolism. The PUFA and combination groups showed elevated bile phospholipid and bile acid levels and a lower cholesterol saturation index. Combination treatment with PUFA and UDCA dissolves cholesterol gallstones in mice by decreasing mucin production, increasing levels of phospholipids and bile acids in bile, and decreasing cholesterol saturation. Further studies of the therapeutic effects of combination PUFA and UDCA treatment in patients with cholesterol gallstones are warranted.

Highlights

Gallstone disease is an important health problem with gastrointestinal sequelae that frequently leads to admission to the hospital[1,2] and has a mortality rate of 0.6%1
We evaluated the therapeutic effects of polyunsaturated fatty acids (PUFA), ursodeoxycholic acid (UDCA), and the combination of PUFA and UDCA in a mouse model of cholesterol gallstones
Gallstones were significantly smaller in the UDCA and combination groups than in the control group (Fig. 1D)

Summary

Introduction

Gallstone disease is an important health problem with gastrointestinal sequelae that frequently leads to admission to the hospital[1,2] and has a mortality rate of 0.6%1. Canadian Eskimos who consume a Western-style diet have an increased prevalence of complications due to cholesterol gallstone disease[8]. Surgical treatments such as cholecystectomy are standard for symptomatic gallstone disease, but there are few medical treatment options. The prevalence of laparoscopic cholecystectomy among gallstone patients is 1.6–12%, and its complication rate can reach 1.2%, with bile duct damage being the major cause of complications[13]. Eskimos, who have a diet rich in fish oil (which contains a high level of omega-3 PUFAs and has two major components, eicosapentaenoic acid [EPA, C20:5n-3] and docosahexaenoic acid [DHA, C22,6n-3])[18], have a lower prevalence of cholesterol gallstones than that of Western populations[19]. We evaluated the therapeutic effects of PUFA, UDCA, and the combination of PUFA and UDCA in a mouse model of cholesterol gallstones

Methods

Results

Conclusion