PBDEs altered gut microbiome and bile acid homeostasis in male C57BL/6 mice

Cindy Yanfei Li, Joseph L. Dempsey, Dongfang Wang, Soo Wan Lee, Kris M. Weigel, Qiang Fei, Deepak Kumar Bhatt, Bhagwat Prasad, Daniel Raftery, Haiwei Gu, Julia Yue Cui

    Research output: Contribution to journalArticle

    10 Citations (Scopus)

    Abstract

    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 µmol/kg), or BDE-99 (100 µmol/kg) once daily for 4 days (n = 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 Akkermansia muciniphila and Erysipelotrichaceae Allobaculum 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 7α-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”.

    Original languageEnglish (US)
    Pages (from-to)1226-1240
    Number of pages15
    JournalDrug Metabolism and Disposition
    Volume46
    Issue number8
    DOIs
    StatePublished - Aug 1 2018

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    Halogenated Diphenyl Ethers
    Bile Acids and Salts
    Inbred C57BL Mouse
    Homeostasis
    Gastrointestinal Contents
    Liver
    Dysbiosis
    Metabolomics
    Corn Oil
    Gastrointestinal Microbiome
    Xenobiotics
    Enzymes
    Biotransformation
    Proteomics
    Anti-Inflammatory Agents
    Down-Regulation

    ASJC Scopus subject areas

    • Pharmacology
    • Pharmaceutical Science

    Cite this

    Li, C. Y., Dempsey, J. L., Wang, D., Lee, S. W., Weigel, K. M., Fei, Q., ... Cui, J. Y. (2018). PBDEs altered gut microbiome and bile acid homeostasis in male C57BL/6 mice. Drug Metabolism and Disposition, 46(8), 1226-1240. https://doi.org/10.1124/dmd.118.081547

    PBDEs altered gut microbiome and bile acid homeostasis in male C57BL/6 mice. / Li, Cindy Yanfei; Dempsey, Joseph L.; Wang, Dongfang; Lee, Soo Wan; Weigel, Kris M.; Fei, Qiang; Bhatt, Deepak Kumar; Prasad, Bhagwat; Raftery, Daniel; Gu, Haiwei; Cui, Julia Yue.

    In: Drug Metabolism and Disposition, Vol. 46, No. 8, 01.08.2018, p. 1226-1240.

    Research output: Contribution to journalArticle

    Li, CY, Dempsey, JL, Wang, D, Lee, SW, Weigel, KM, Fei, Q, Bhatt, DK, Prasad, B, Raftery, D, Gu, H & Cui, JY 2018, 'PBDEs altered gut microbiome and bile acid homeostasis in male C57BL/6 mice', Drug Metabolism and Disposition, vol. 46, no. 8, pp. 1226-1240. https://doi.org/10.1124/dmd.118.081547
    Li, Cindy Yanfei ; Dempsey, Joseph L. ; Wang, Dongfang ; Lee, Soo Wan ; Weigel, Kris M. ; Fei, Qiang ; Bhatt, Deepak Kumar ; Prasad, Bhagwat ; Raftery, Daniel ; Gu, Haiwei ; Cui, Julia Yue. / PBDEs altered gut microbiome and bile acid homeostasis in male C57BL/6 mice. In: Drug Metabolism and Disposition. 2018 ; Vol. 46, No. 8. pp. 1226-1240.
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    abstract = "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 µmol/kg), or BDE-99 (100 µmol/kg) once daily for 4 days (n = 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 Akkermansia muciniphila and Erysipelotrichaceae Allobaculum 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 7α-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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    AU - Weigel, Kris M.

    AU - Fei, Qiang

    AU - Bhatt, Deepak Kumar

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