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

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 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".

Transcriptomic profiling of PBDE-exposed HepaRG cells unveils critical lncRNA- PCG pairs involved in intermediary metabolism

“…We identified a total of 13,204 genes that were uniquely expressed by at least one of the four exposures groups, and that PBDEs activate both PXR and CAR pathways in human HepaRG cells. Consistent with the result in this study, previous studies have shown that PBDEs activate PXR/CAR pathways in mouse livers [21]. With regards to CAR pathway mediation, a previous study demonstrated the activation of CAR pathways through BDE-47 in human primary hepatocytes [12].…”

“…With regards to the sirtuin signaling pathway, exposure to pollutants can affect SIRT1 expression; this can affect the expression of downstream proteins and result in toxic damage. Upregulation of SIRT1 expression is protective against the toxicity of pollutants [21]. In our current study, SIRT1 was significantly downregulated in HepaRG cells exposed to BDE-99, suggesting that this PBDE can leave hepatocytes vulnerable to toxic attacks.…”

“…These increasing levels of bile acids corresponded to an increased abundance of bacterial and their resulting microbial enzymes. Unconjugated bile acids are generally thought to be more toxic than their conjugated counterparts; an excess of unconjugated bile acids could lead to impaired liver function and cholestasis [21]. With regards to the sirtuin signaling pathway, exposure to pollutants can affect SIRT1 expression; this can affect the expression of downstream proteins and result in toxic damage.…”

“…All data is available on the Gene Expression Omnibus (GEO) data (accession number: GSE143260) The library construction and sequencing were conducted using a similar method as described before [21]. The workflow for the analysis is outlined in Fig 1. FASTQ files with paired-end sequence reads were mapped to the human genome (hg19) using HISAT (Hierarchical Indexing for Spliced Alignment of Transcripts).…”

Capturing the Complex Interplay Between Drugs and the Intestinal Microbiome

“…For example, 16S rRNA sequencing has been applied to study (i) the shift in intestinal microbiomes before and after drinking GT 4 and (ii) the impact of polybrominated diphenyl ethers, persistent environmental contaminants, on the regulation of primary bile acids metabolized by the mouse gut microbiome. 5 Although 16S rRNA sequencing has a relatively low cost per sample, there are many challenges associated with processing and interpreting the immense number of resulting DNA sequences. As is common for observational studies, it is often impossible to distinguish correlation from causation in microbiome surveys.…”