Gut microbiota inhibit Asbt-dependent intestinal bile acid reabsorption via Gata4

Carolien Out, Jay V. Patankar, Marcela Doktorova, Marije Boesjes, Trijnie Bos, Sanna de Boer, Rick Havinga, Henk Wolters, Renze Boverhof, Theo H. van Dijk, Anna Smoczek, Andre Bleich, Vinay Sachdev, Dagmar Kratky, Folkert Kuipers, Henkjan J. Verkade, Albert K. Groen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

57 Citations (Scopus)

Abstract

Background & Aims: 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. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Original languageEnglish
Pages (from-to)697-704
Number of pages8
JournalJournal of Hepatology
Volume63
Issue number3
DOIs
Publication statusPublished - Sep-2015

Keywords

  • Gut microbiota
  • Intestinal bacteria
  • Antibiotic treatment
  • Enterohepatic circulation
  • Germfree
  • Fgf15
  • Asbt
  • Gata4
  • Bile acid reabsorption
  • Bile acid synthesis
  • Cyp7a1
  • LIVER MICROSOMAL METABOLISM
  • MOUSE SMALL-INTESTINE
  • GERMFREE RATS
  • CONVENTIONAL RATS
  • ENTEROHEPATIC CIRCULATION
  • CHOLESTEROL
  • STEROIDS
  • MICE
  • ABSORPTION
  • EXPRESSION

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