title: Altered FXR signalling is associated with bile acid dysmetabolism in short bowel syndrome-associated liver disease.
abstract: OBJECTIVE
  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.
authors.affiliation: Intestinal Failure and Clinical Nutrition Research Group, Murdoch Childrens Research Institute, Parkville, Victoria, Australia. Electronic address: prue.pereira@mcri.edu.au.
authors.forename: Prue M
authors.initials: PM
authors.lastname: Pereira-Fantini
authors.affiliation: Intestinal Failure and Clinical Nutrition Research Group, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
authors.forename: Susan
authors.initials: S
authors.lastname: Lapthorne
authors.affiliation: Alimentary Pharmabiotic Centre, Cork, Ireland.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Joyce
authors.affiliation: Intestinal Failure and Clinical Nutrition Research Group, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Dellios
authors.affiliation: Intestinal Failure and Clinical Nutrition Research Group, Murdoch Childrens Research Institute, Parkville, Victoria, Australia; Department of Surgery, Monash Medical Centre, Clayton, Victoria, Australia.
authors.forename: Guineva
authors.initials: G
authors.lastname: Wilson
authors.affiliation: School of Microbiology, University College Cork, Cork, Ireland; Teagasc Food Research Centre, Moorepark, Fermoy, County Cork, Ireland.
authors.forename: Fiona
authors.initials: F
authors.lastname: Fouhy
authors.affiliation: Intestinal Failure and Clinical Nutrition Research Group, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Thomas
authors.affiliation: Intestinal Failure and Clinical Nutrition Research Group, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
authors.forename: Michelle
authors.initials: M
authors.lastname: Scurr
authors.affiliation: Alimentary Pharmabiotic Centre, Cork, Ireland.
authors.forename: Colin
authors.initials: C
authors.lastname: Hill
authors.affiliation: Alimentary Pharmabiotic Centre, Cork, Ireland.
authors.forename: Cormac G M
authors.initials: CG
authors.lastname: Gahan
authors.affiliation: Alimentary Pharmabiotic Centre, Cork, Ireland; Teagasc Food Research Centre, Moorepark, Fermoy, County Cork, Ireland.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Cotter
authors.affiliation: Prince Henry's Institute for Medical Research, Clayton, Victoria, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Fuller
authors.affiliation: Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital, Parkville, Victoria, Australia; Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia; Gastro and Food Allergy Group, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
authors.forename: Winita
authors.initials: W
authors.lastname: Hardikar
authors.affiliation: Intestinal Failure and Clinical Nutrition Research Group, Murdoch Childrens Research Institute, Parkville, Victoria, Australia; Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital, Parkville, Victoria, Australia; Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Bines
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008099:Liver / Q000473:pathology; D008107:Liver Diseases / Q000209:etiology* / Q000378:metabolism* / Q000382:microbiology; D064307:Microbiota; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012778:Short Bowel Syndrome / Q000150:complications* / Q000378:metabolism* / Q000382:microbiology; D015398:Signal Transduction; D034421:Sus scrofa; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated
keywords: Bile acids and salts; Farnesoid X receptor NR1H4; Gut microbiota; Intestinal failure associated liver disease; Liver diseases; Short bowel syndrome