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

• Published in: Drug metabolism and disposition Vol. 46; no. 8; pp. 1226 - 1240
• Main Authors: Li, Cindy Yanfei, Dempsey, Joseph L., Wang, Dongfang, Lee, SooWan, Weigel, Kris M., Fei, Qiang, Bhatt, Deepak Kumar, Prasad, Bhagwat, Raftery, Daniel, Gu, Haiwei, Cui, Julia Yue
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2018; American Society for Pharmacology and Experimental Therapeutics, Inc; The American Society for Pharmacology and Experimental Therapeutics
• Subjects: Animals; Bile; Bile acids; Bile Acids and Salts - metabolism; Biodiversity; Biotransformation; Biotransformation - drug effects; Congeners; Contaminants; Corn oil; Digestive system; Down-Regulation - drug effects; Dysbacteriosis; Dysbiosis - drug therapy; Dysbiosis - metabolism; Enzymes; Ethers; Gastrointestinal Microbiome - drug effects; Gastrointestinal tract; Germfree; Halogenated Diphenyl Ethers - pharmacology; Homeostasis; Homeostasis - drug effects; Hydroxylation - drug effects; Inflammation; Intestinal microflora; Intestine; Intestine, Large - drug effects; Intestine, Large - metabolism; Lipophilic; Liver; Liver - drug effects; Liver - metabolism; Male; Metabolomics; Metabolomics - methods; Mice; Mice, Inbred C57BL; Microbiomes; Microbiota; Microorganisms; Oils & fats; Organs; Polybrominated diphenyl ethers; Proteomics; Receptors; RNA, Ribosomal, 16S - metabolism; rRNA 16S; Signal Transduction - drug effects; FXR; Bsep; T-α/βMCA; bai; Oatp; PXR; LCA-D4; BSA; LC-MS/MS; BDE-99; ANOVA; BAs; KEGG; P450; qPCR; GCDCA-D4; QIIME; GF; PBDEs; LIC; IS; MCA; ACN; DCA-D4; SIC; GCA-D4; CA-D4; BDE-47; CV; Akr1c14; PICRUSt; bsh; Ntcp
• DOI: 10.1124/dmd.118.081547
• ISSN: 0090-9556; 1521-009X

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”.