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Research ArticleSpecial Section on Drug Metabolism and the Microbiome

Importance of Large Intestine in Regulating Bile Acids and Glucagon-Like Peptide-1 in Germ-Free Mice

Felcy Pavithra Selwyn, Iván L. Csanaky, Youcai Zhang and Curtis D. Klaassen
Drug Metabolism and Disposition October 2015, 43 (10) 1544-1556; DOI: https://doi.org/10.1124/dmd.115.065276
Felcy Pavithra Selwyn
Departments of Pharmacology, Toxicology, and Therapeutics (F.P.S., Y.Z.) and Internal Medicine (I.L.C., C.D.K.), University of Kansas Medical Center, Kansas City, Kansas.
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Iván L. Csanaky
Departments of Pharmacology, Toxicology, and Therapeutics (F.P.S., Y.Z.) and Internal Medicine (I.L.C., C.D.K.), University of Kansas Medical Center, Kansas City, Kansas.
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Youcai Zhang
Departments of Pharmacology, Toxicology, and Therapeutics (F.P.S., Y.Z.) and Internal Medicine (I.L.C., C.D.K.), University of Kansas Medical Center, Kansas City, Kansas.
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Curtis D. Klaassen
Departments of Pharmacology, Toxicology, and Therapeutics (F.P.S., Y.Z.) and Internal Medicine (I.L.C., C.D.K.), University of Kansas Medical Center, Kansas City, Kansas.
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Abstract

It is known that 1) elevated serum bile acids (BAs) are associated with decreased body weight, 2) elevated glucagon-like peptide-1 (GLP-1) levels can decrease body weight, and 3) germ-free (GF) mice are resistant to diet-induced obesity. The purpose of this study was to test the hypothesis that a lack of intestinal microbiota results in more BAs in the body, resulting in increased BA-mediated transmembrane G protein–coupled receptor 5 (TGR5) signaling and increased serum GLP-1 as a mechanism of resistance of GF mice to diet-induced obesity. GF mice had 2- to 4-fold increased total BAs in the serum, liver, bile, and ileum. Fecal excretion of BAs was 63% less in GF mice. GF mice had decreased secondary BAs and increased taurine-conjugated BAs, as anticipated. Surprisingly, there was an increase in non–12α-OH BAs, namely, β-muricholic acid, ursodeoxycholic acid (UDCA), and their taurine conjugates, in GF mice. Further, in vitro experiments confirmed that UDCA is a primary BA in mice. There were minimal changes in the mRNA of farnesoid X receptor target genes in the ileum (Fibroblast growth factor 15, small heterodimer protein, and ileal bile acid–binding protein), in the liver (small heterodimer protein, liver receptor homolog-1, and cytochrome P450 7a1), and BA transporters (apical sodium dependent bile acid transporter, organic solute transporter α, and organic solute transporter β) in the ileum of GF mice. Surprisingly, there were marked increases in BA transporters in the large intestine. Increased GLP-1 levels and gallbladder size were observed in GF mice, suggesting activation of TGR5 signaling. In summary, the GF condition results in increased expression of BA transporters in the colon, resulting in 1) an increase in total BA concentrations in tissues, 2) a change in BA composition to favor an increase in non–12α-OH BAs, and 3) activation of TGR5 signaling with increased gallbladder size and GLP-1.

Footnotes

    • Received May 4, 2015.
    • Accepted July 20, 2015.
  • ↵1 Current affiliation: Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy Hospital & Clinics, Kansas City, Missouri.

  • ↵2 Current affiliation: School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China.

  • ↵3 Current affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington.

  • This research was supported by the National Institutes of Health [Grants ES09649, ES019487, and GM111381].

  • This research is part of the thesis of Dr. Felcy Pavithra Selwyn titled “Alterations in bile acid homeostasis and drug metabolism in germ-free mice.” A portion of this research has been presented at the following meetings: Selwyn F and Klaassen CD (2012) Characterization of bile acid homeostasis in germ-free mice Selwyn FP, Zhang Y and Klaassen CD. Experimental Biology 2012; 2012 Apr 21–25; San Diego, CA. American Society of Pharmacotherapy and Experimental Therapeutics, Bethesda, MD; (2012) Characterization of bile acid homeostasis in germ-free mice. Bile Acid-Mediated Integration of Metabolism and Liver Disease: A Research Workshop; 2012 Jun 8; Bethesda, MD. National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD.

  • dx.doi.org/10.1124/dmd.115.065276.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (10)
Drug Metabolism and Disposition
Vol. 43, Issue 10
1 Oct 2015
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Research ArticleSpecial Section on Drug Metabolism and the Microbiome

Bile Acids in Germ-Free Mice

Felcy Pavithra Selwyn, Iván L. Csanaky, Youcai Zhang and Curtis D. Klaassen
Drug Metabolism and Disposition October 1, 2015, 43 (10) 1544-1556; DOI: https://doi.org/10.1124/dmd.115.065276

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Research ArticleSpecial Section on Drug Metabolism and the Microbiome

Bile Acids in Germ-Free Mice

Felcy Pavithra Selwyn, Iván L. Csanaky, Youcai Zhang and Curtis D. Klaassen
Drug Metabolism and Disposition October 1, 2015, 43 (10) 1544-1556; DOI: https://doi.org/10.1124/dmd.115.065276
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