Antibacterial Drug Treatment Increases Intestinal Bile Acid Absorption &lt;i&gt;via&lt;/i&gt; Elevated Levels of Ileal Apical Sodium-Dependent Bile Acid Transporter but Not Organic Solute Transporter α Protein

Miyata, Masaaki; Hayashi, Kenjiro; Yamakawa, Hiroki; Yamazoe, Yasushi; Yoshinari, Kouichi

doi:10.1248/bpb.b14-00640

Cited by 7 publications

(2 citation statements)

References 24 publications

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“…4-7). These findings are consistent with previous studies (Sayin et al, 2013;Hu et al, 2014;Miyata et al, 2015;Selwyn et al, 2015b). T-CA was increased in all compartments, except liver.…”

Section: Discussionsupporting

confidence: 93%

PBDEs Altered Gut Microbiome and Bile Acid Homeostasis in Male C57BL/6 Mice

Dempsey

Wang

et al. 2018

Drug Metab Dispos

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Polybrominated diphenyl ethers (PBDEs) are persistent environmental contaminants with well characterized toxicities in host organs. Gut microbiome is increasingly recognized as an important regulator of xenobiotic biotransformation; however, little is known about its interactions with PBDEs. Primary bile acids (BAs) are metabolized by the gut microbiome into more lipophilic secondary BAs that may be absorbed and interact with certain host receptors. The goal of this study was to test our hypothesis that PBDEs cause dysbiosis and aberrant regulation of BA homeostasis. Nine-week-old male C57BL/6 conventional (CV) and germ-free (GF) mice were orally gavaged with corn oil (10 mg/kg), BDE-47 (100 mol/kg), or BDE-99 (100mol/kg) once daily for 4 days ( = 3-5/group). Gut microbiome was characterized using 16S rRNA sequencing of the large intestinal content in CV mice. Both BDE-47 and BDE-99 profoundly decreased the alpha diversity of gut microbiome and differentially regulated 45 bacterial species. Both PBDE congeners increased and Erysipelotrichaceae spp., which have been reported to have anti-inflammatory and antiobesity functions. Targeted metabolomics of 56 BAs was conducted in serum, liver, and small and large intestinal content of CV and GF mice. BDE-99 increased many unconjugated BAs in multiple biocompartments in a gut microbiota-dependent manner. This correlated with an increase in microbial 7-dehydroxylation enzymes for secondary BA synthesis and increased expression of host intestinal transporters for BA absorption. Targeted proteomics showed that PBDEs downregulated host BA-synthesizing enzymes and transporters in livers of CV but not GF mice. In conclusion, there is a novel interaction between PBDEs and the endogenous BA-signaling through modification of the "gut-liver axis".

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“…4-7). These findings are consistent with previous studies (Sayin et al, 2013;Hu et al, 2014;Miyata et al, 2015;Selwyn et al, 2015b). T-CA was increased in all compartments, except liver.…”

Section: Discussionsupporting

confidence: 93%

PBDEs Altered Gut Microbiome and Bile Acid Homeostasis in Male C57BL/6 Mice

Dempsey

Wang

et al. 2018

Drug Metab Dispos

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“…The ileal BA uptake transporter (Asbt) is thought to be responsible for the reabsorption of most of the BAs from the intestine (Dawson et al, 2003). It is known that antibiotics decrease the number of intestinal bacteria, increase intestinal BA absorption (Miyata et al, 2015), decrease fecal BA excretion, and increase hepatic BA concentrations (Hu et al, 2014;Zhang et al, 2014), with an increase in ileal Asbt expression. On the contrary, Asbt-null mice have limited enterohepatic circulation of BAs, increased fecal BA excretion, and decreased BA pool size (Dawson et al, 2003), which is just the opposite of what is observed in GF mice.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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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-12a-OH BAs, namely, b-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 a, and organic solute transporter b) 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-12a-OH BAs, and 3) activation of TGR5 signaling with increased gallbladder size and GLP-1.

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Bile acid homeostasis paradigm and its connotation with cholestatic liver diseases

Yang

Khan

et al. 2019

Drug Discovery Today

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Antibacterial Drug Treatment Increases Intestinal Bile Acid Absorption <i>via</i> Elevated Levels of Ileal Apical Sodium-Dependent Bile Acid Transporter but Not Organic Solute Transporter α Protein

Cited by 7 publications

References 24 publications

PBDEs Altered Gut Microbiome and Bile Acid Homeostasis in Male C57BL/6 Mice

PBDEs Altered Gut Microbiome and Bile Acid Homeostasis in Male C57BL/6 Mice

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

Bile acid homeostasis paradigm and its connotation with cholestatic liver diseases

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