Novel Interactions between Gut Microbiome and Host Drug‐processing Genes Modify the Hepatic Metabolism of the Environmental Chemicals PBDEs
Authors: Li Cindy Yanfei , Cade Sara , Schultz Irvin , Kuo Li‐Jung , Bammler Theo K. , Cui Julia Yue 
Published: November 2023

The gut microbiome is often termed “the second genome” because it can interact with the host genome to regulate important metabolic pathways such as xenobiotic biotransformation and nutrient homeostasis. The polybrominated diphenyl ethers (PBDEs) that are previously used as flame retardants are among the most abundant and persistent environmental contaminants in the human population. Especially, the 2,2′,4,4′‐tetrabromodiphenyl (BDE‐47) and 2,2′,4,4′,5‐pentabromodiphenyl ether (BDE‐99) congeners are prevalent in seafood and breast milk at worrisome levels. Very little is known about how the gut microbiome affects the hepatic metabolism of PBDEs in vivo. Therefore, the goal of the present study was to utilize germ‐free (GF) mice to investigate the interactions between the gut microbiome and the host hepatic biotransformation pathways of PBDEs. Three‐month‐old male C57BL/6J conventional (CV) or GF mice were treated with vehicle (corn oil, 10ml/kg, oral gavage), BDE‐47 (100μmol/kg) or BDE‐99 (100μmol/kg) once daily for four days. The hepatic transcriptome was determined using RNA‐Seq. The differentially expressed drug‐processing genes (DPGs) were defined as FDR< 0.05 in at least one of the chemical‐treated groups as compared to the vehicle‐treated group. No apparent hepatic injury was observed in any treatment groups (serum alanine aminotransferase and H&E staining). PBDE targeted metabolomics (GC‐MS‐NCI) revealed that the major hydroxylated PBDE metabolites in livers of both CV and GF mice were 5‐OH‐BDE‐47 and 5′‐OH‐BDE‐99 for BDE‐47 and BDE‐99, respectively. Following BDE‐47 treatment, livers of GF mice had higher levels of 5‐OH‐BDE‐47, and lower levels of 4 other minor metabolites (3‐OH‐BDE‐47, 4′‐OH‐BDE‐49, 4′‐OH‐BDE‐17, and 2′‐OH‐BDE‐28) than CV mice. Following BDE‐99 treatment, livers of GF mice had lower levels of 4 minor metabolites (4′‐OH‐BDE‐101, 4′‐OH‐BDE‐49, 6‐OH‐BDE‐85, and 4′‐OH‐BDE‐103), as compared to livers of PBDE‐treated CV mice. RNA‐Seq demonstrated that certain DPGs were differentially regulated in livers of GF mice under both basal and PBDE‐treated conditions. For example, under basal condition, many Cyp2c genes (Cyp2c40, 2c50, 2c54, 2c67, 2c68, 2c69, and 2c70) were up‐regulated, whereas Cyp3a genes (Cyp3a11, 3a16, 3a41a, 3a41b, 3a44, and 3a59) were down‐regulated in GF mice compared with CV mice. Interestingly, after BDE‐99 treatment, more Cyp2d genes (Cyp2d9, 2d10, 2d12, 2d26, and 2d40) were significantly down‐regulated in GF condition. Moreover, the lack of gut microbiome sensitized the liver to BDE‐99 mediated up‐regulation of many DPGs such as Phase I (Cyp1a, 2a4, 2a5, 2b10, 2b13, 2c29, 2c37, 2c50, 2c54, 2c55, 2d13, 2j9, 3a11, 3a16, 3a25, 3a41a, 3a41b, 3a44, and 3a59), Phase II (Ugt2b1, Ugt2b5, Ugt2b34, Ugt2b35, Ugt3b36, Ugt3b38, Ugdh and Ugp2; Sult1d1, Sult1e1, Papss2; Gsta1, Gsta2, Gstm1, Gstm2, Gstm3, Gstm4, Gstt3, and Gclc), and transporter (Slco1a4, Slco1b2, Abcb1a, Abcc2, Abcc4, and Abcc10) genes. In summary, our study demonstrated a novel interaction between the gut microbiome and the hepatic biotransformation of PBDEs in vivo.