Altered FXR signalling is associated with bile acid dysmetabolism in short bowel syndrome-associated liver disease

被引:75
作者
Pereira-Fantini, Prue M. [1 ]
Lapthorne, Susan [1 ]
Joyce, Susan A. [2 ]
Dellios, Nicole L. [1 ]
Wilson, Guineva [1 ,3 ]
Fouhy, Fiona [4 ,5 ]
Thomas, Sarah L. [1 ]
Scurr, Michelle [1 ]
Hill, Colin [2 ]
Gahan, Cormac G. M. [2 ]
Cotter, Paul D. [2 ,5 ]
Fuller, Peter J. [6 ]
Hardikar, Winita [7 ,8 ,9 ]
Bines, Julie E. [1 ,7 ,8 ]
机构
[1] Royal Childrens Hosp, Murdoch Childrens Res Inst, Intestinal Failure & Clin Nutr Res Grp, Parkville, Vic 3052, Australia
[2] Alimentary Pharmabiot Ctr, Cork, Ireland
[3] Monash Med Ctr, Dept Surg, Clayton, Vic 3168, Australia
[4] Natl Univ Ireland Univ Coll Cork, Sch Microbiol, Cork, Ireland
[5] Teagasc Food Res Ctr, Fermoy, County Cork, Ireland
[6] Prince Henrys Inst Med Res, Clayton, Vic, Australia
[7] Royal Childrens Hosp, Dept Gastroenterol & Clin Nutr, Parkville, Vic 3052, Australia
[8] Univ Melbourne, Dept Paediat, Parkville, Vic 3052, Australia
[9] Murdoch Childrens Res Inst, Gastro & Food Allergy Grp, Parkville, Vic, Australia
基金
英国医学研究理事会; 爱尔兰科学基金会;
关键词
Short bowel syndrome; Liver diseases; Intestinal failure associated liver disease; Farnesoid X receptor NR1H4; Bile acids and salts; Gut microbiota; FARNESOID-X-RECEPTOR; SMALL HETERODIMER PARTNER; PARENTERAL-NUTRITION; METABOLISM; MICROBIOTA; ACTIVATION; HOMEOSTASIS; EXPRESSION; CYP7A1; SERUM;
D O I
10.1016/j.jhep.2014.06.025
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Background & Aims: Despite the mortality associated with liver disease observed in patients with short bowel syndrome (SBS), mechanisms underlying the development of SBS-associated liver disease (SBS-ALD) are poorly understood. This study examines the impact of bacterially-mediated bile acid (BA) dysmetabolism on farnesoid X receptor (FXR) signalling pathways and clinical outcome in a piglet model of SBS-ALD. Methods: 4-week old piglets underwent 75% small bowel resection (SBR) or sham operation. Liver histology and hepatic inflammatory gene expression were examined. Abundance of BA biotransforming bacteria was determined and metabolomic studies detailed the alterations in BA composition of stool, portal serum and bile samples. Gene expression of intestinal and hepatic FXR target genes and small heterodimer partner (SHP) transrepression targets were assessed. Results: Histological evidence of SBS-ALD included liver bile duct proliferation, hepatocyte ballooning and fibrosis. Inflammatory gene expression was increased. Microbiota changes included a 10-fold decrease in Clostridium and a two-fold decrease in Bacteroides in SBS-ALD piglets. BA composition was altered and reflected a primary BA dominant composition. Intestinal and hepatic regulation of BA synthesis was characterised by a blunted intestinal FXR activation response and a failure of SHP to repress key hepatic targets. Conclusions: We propose a pathological scenario in which microbial dysbiosis following SBR results in significant BA dysmetabolism and consequent outcomes including steatorrhoea, persistent diarrhoea and liver damage. Furthermore alterations in BA composition may have contributed to the observed disturbance in FXR-mediated signalling pathways. These findings provide an insight into the complex mechanisms mediating the development of liver disease in patients with SBS. Crown copyright (C) 2014 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver. All rights reserved.
引用
收藏
页码:1115 / 1125
页数:11
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