Gut microbiota inhibit Asbt-dependent intestinal bile acid reabsorption via Gata4
- PMID: 26022694
- PMCID: PMC5293168
- DOI: 10.1016/j.jhep.2015.04.030
Gut microbiota inhibit Asbt-dependent intestinal bile acid reabsorption via Gata4
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.
Keywords: Antibiotic treatment; Asbt; Bile acid reabsorption; Bile acid synthesis; Cyp7a1; Enterohepatic circulation; Fgf15; Gata4; Germfree; Gut microbiota; Intestinal bacteria.
Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Conflict of interest statement
The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
Figures
Similar articles
-
Apical sodium-dependent bile acid transporter, drug target for bile acid related diseases and delivery target for prodrugs: Current and future challenges.Pharmacol Ther. 2020 Aug;212:107539. doi: 10.1016/j.pharmthera.2020.107539. Epub 2020 Mar 20. Pharmacol Ther. 2020. PMID: 32201314 Review.
-
An important intestinal transporter that regulates the enterohepatic circulation of bile acids and cholesterol homeostasis: The apical sodium-dependent bile acid transporter (SLC10A2/ASBT).Clin Res Hepatol Gastroenterol. 2017 Oct;41(5):509-515. doi: 10.1016/j.clinre.2017.02.001. Epub 2017 Mar 21. Clin Res Hepatol Gastroenterol. 2017. PMID: 28336180 Review.
-
Antibacterial drug treatment increases intestinal bile acid absorption via elevated levels of ileal apical sodium-dependent bile acid transporter but not organic solute transporter α protein.Biol Pharm Bull. 2015;38(3):493-6. doi: 10.1248/bpb.b14-00640. Epub 2014 Dec 27. Biol Pharm Bull. 2015. PMID: 25757934
-
Conditional Gata4 deletion in mice induces bile acid absorption in the proximal small intestine.Gut. 2010 Jul;59(7):888-95. doi: 10.1136/gut.2009.204990. Gut. 2010. PMID: 20581237 Free PMC article.
-
Cholesterol dependent downregulation of mouse and human apical sodium dependent bile acid transporter (ASBT) gene expression: molecular mechanism and physiological consequences.Gut. 2006 Sep;55(9):1321-31. doi: 10.1136/gut.2005.085555. Epub 2006 Feb 16. Gut. 2006. PMID: 16484503 Free PMC article.
Cited by
-
Gut microbiota depletion aggravates bile acid-induced liver pathology in mice with a human-like bile acid composition.Clin Sci (Lond). 2023 Nov 15;137(21):1637-1650. doi: 10.1042/CS20230812. Clin Sci (Lond). 2023. PMID: 37910096 Free PMC article.
-
Gut microbiome and metabolic-associated fatty liver disease: Current status and potential applications.World J Hepatol. 2023 Jul 27;15(7):867-882. doi: 10.4254/wjh.v15.i7.867. World J Hepatol. 2023. PMID: 37547030 Free PMC article. Review.
-
The interplay between bile acids and mucosal adaptive immunity.PLoS Pathog. 2023 Jun 22;19(6):e1011356. doi: 10.1371/journal.ppat.1011356. eCollection 2023 Jun. PLoS Pathog. 2023. PMID: 37347728 Free PMC article. No abstract available.
-
Connecting the Gut Microbiota and Neurodegenerative Diseases: the Role of Bile Acids.Mol Neurobiol. 2023 Aug;60(8):4618-4640. doi: 10.1007/s12035-023-03340-9. Epub 2023 May 1. Mol Neurobiol. 2023. PMID: 37121952 Review.
-
Bile Acids and Biliary Fibrosis.Cells. 2023 Mar 2;12(5):792. doi: 10.3390/cells12050792. Cells. 2023. PMID: 36899928 Free PMC article. Review.
References
-
- Kitahara M, Takamine F, Imamura T, et al. Clostridium hiranonis sp. nov., a human intestinal bacterium with bile acid 7alpha-dehydroxylating activity. Int J Syst Evol Microbiol. 2001;51:39–44. - PubMed
-
- Ridlon JM, Kang DJ, Hylemon PB. Bile salt biotransformations by human intestinal bacteria. J Lipid Res. 2006;47:241–259. - PubMed
-
- Batta AK, Salen G, Arora R, et al. Side chain conjugation prevents bacterial 7-dehydroxylation of bile acids. J Biol Chem. 1990;265:10925–10928. - PubMed
-
- Hagenbuch B, Dawson P. The sodium bile salt cotransport family SLC10. Pflugers Arch. 2004;447:566–570. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials