Type

Journal Article

Authors

Julie E Bines
Winita Hardikar
Peter J Fuller
Paul D. Cotter
Cormac G M Gahan
Colin Hill
Michelle Scurr
Sarah L Thomas
Fiona Fouhy
Guineva Wilson
and 4 others

Subjects

Biochemistry

Topics
bile short bowel syndrome liver disease signalling pathways acid target genes signalling gene expression

Altered FXR signalling is associated with bile acid dysmetabolism in short bowel syndrome-associated liver disease. (2013)

Abstract 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. 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. 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. 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.
Collections Ireland -> Teagasc -> PubMed

Full list of authors on original publication

Julie E Bines, Winita Hardikar, Peter J Fuller, Paul D. Cotter, Cormac G M Gahan, Colin Hill, Michelle Scurr, Sarah L Thomas, Fiona Fouhy, Guineva Wilson and 4 others

Experts in our system

1
Julie E Bines
Teagasc
Total Publications: 5
 
2
Peter J. Fuller
University College Cork
Total Publications: 3
 
3
Paul D. Cotter
Teagasc
Total Publications: 253
 
4
Cormac G M Gahan
University College Cork
Total Publications: 109
 
5
Colin Hill
University College Cork
Total Publications: 351
 
6
Fiona Fouhy
Teagasc
Total Publications: 27