title: Gut microbiota inhibit Asbt-dependent intestinal bile acid reabsorption via Gata4.
abstract: OBJECTIVE
  Regulation of bile acid homeostasis in mammals is a complex process regulated via extensive cross-talk between liver, intestine and intestinal microbiota. Here we studied the effects of gut microbiota on bile acid homeostasis in mice.
  
  
  METHODS
  Bile acid homeostasis was assessed in four mouse models. Germfree mice, conventionally-raised mice, Asbt-KO mice and intestinal-specific Gata4-iKO mice were treated with antibiotics (bacitracin, neomycin and vancomycin; 100 mg/kg) for five days and subsequently compared with untreated mice.
  
  
  RESULTS
  Attenuation of the bacterial flora by antibiotics strongly reduced fecal excretion and synthesis of bile acids, but increased the expression of the bile acid synthesis enzyme CYP7A1. Similar effects were seen in germfree mice. Intestinal bile acid absorption was increased and accompanied by increases in plasma bile acid levels, biliary bile acid secretion and enterohepatic cycling of bile acids. In the absence of microbiota, the expression of the intestinal bile salt transporter Asbt was strongly increased in the ileum and was also expressed in more proximal parts of the small intestine. Most of the effects of antibiotic treatment on bile acid homeostasis could be prevented by genetic inactivation of either Asbt or the transcription factor Gata4.
  
  
  CONCLUSIONS
  Attenuation of gut microbiota alters Gata4-controlled expression of Asbt, increasing absorption and decreasing synthesis of bile acids. Our data support the concept that under physiological conditions microbiota stimulate Gata4, which suppresses Asbt expression, limiting the expression of this transporter to the terminal ileum. Our studies expand current knowledge on the bacterial control of bile acid homeostasis.
authors.affiliation: Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Carolien
authors.initials: C
authors.lastname: Out
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria; Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Jay V
authors.initials: JV
authors.lastname: Patankar
authors.affiliation: Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Marcela
authors.initials: M
authors.lastname: Doktorova
authors.affiliation: Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Marije
authors.initials: M
authors.lastname: Boesjes
authors.affiliation: Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Trijnie
authors.initials: T
authors.lastname: Bos
authors.affiliation: Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Sanna
authors.initials: S
authors.lastname: de Boer
authors.affiliation: Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Rick
authors.initials: R
authors.lastname: Havinga
authors.affiliation: Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Henk
authors.initials: H
authors.lastname: Wolters
authors.affiliation: Department of Laboratory Medicine, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Renze
authors.initials: R
authors.lastname: Boverhof
authors.affiliation: Department of Laboratory Medicine, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Theo H
authors.initials: TH
authors.lastname: van Dijk
authors.affiliation: Zentrales Tierlaboratorium und Institut für Versuchstierkunde, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Smoczek
authors.affiliation: Zentrales Tierlaboratorium und Institut für Versuchstierkunde, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Bleich
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Vinay
authors.initials: V
authors.lastname: Sachdev
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kratky
authors.affiliation: Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
authors.affiliation: Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Henkjan J
authors.initials: HJ
authors.lastname: Verkade
authors.affiliation: Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Laboratory Medicine, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. Electronic address: a.k.groen@umcg.nl.
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001647:Bile Acids and Salts / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics; D050991:GATA4 Transcription Factor / Q000502:physiology*; D000069196:Gastrointestinal Microbiome / Q000502:physiology*; D006706:Homeostasis; D007408:Intestinal Absorption; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D029363:Organic Anion Transporters, Sodium-Dependent / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D027981:Symporters / Q000502:physiology*
chemical_list: D000900:Anti-Bacterial Agents; D001647:Bile Acids and Salts; D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger; D027981:Symporters; C071908:sodium-bile acid cotransporter; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse
keywords: Antibiotic treatment; Asbt; Bile acid reabsorption; Bile acid synthesis; Cyp7a1; Enterohepatic circulation; Fgf15; Gata4; Germfree; Gut microbiota; Intestinal bacteria