Polychlorinated biphenyls (PCBs) are ubiquitously detected in the environment and have been linked to metabolic diseases. The liver serves as a central hub for the metabolism of xenobiotics and endogenous metabolites. Gut dysbiosis is recognized as a critical regulator of disease susceptibility, however, little is known regarding how PCBs and gut microbiome interact to modulate the interface between xenobiotic and intermediary metabolism. We hypothesized that the gut microbiome regulates PCBs-mediated changes in the metabolic fingerprints and hepatic transcriptome. Ninety-day-old female conventional (CV) and germ-free (GF) C57BL/6 mice were orally exposed to the PCB Fox River Mixture (synthetic PCB mixture, 6 or 30 mg/kg) or corn oil (vehicle control, 10 ml/kg), once daily for 3 consecutive days. Organs were collected 24 hours after the final dose. RNA-Seq was conducted on liver, and endogenous aqueous metabolites (amino acids, carbohydrates, and nucleotides) were measured in liver and serum by LC-MS. The primary factor in clustering the transcriptomic and metabolomic signatures within the same exposure was by enterotype. The numbers of PCB-regulated genes were higher in CV than in GF conditions. The prototypical target genes of the major xenobiotic-sensing transcription factors AhR, PXR, and CAR were more readily up-regulated by PCBs in CV than in GF conditions, indicating the effect of PCBs on the hepatic transcriptome act partly through the gut microbiome. Xenobiotic and steroid metabolism pathways were up-regulated, whereas response to incorrect proteins pathway was down-regulated by PCBs in a gut microbiome-dependent manner. At the high PCB dose, NADP and arginine appear to interact with drug-metabolizing enzymes (Cyp1-3 family, DhcR7, and Nqo1), which are highly correlated with Anaerotruncus and Roseburia in CV mice, providing a novel explanation of gut-liver interaction in toxicant exposures. In GF exposure groups, hepatic glucose was down-regulated, whereas fructose 6-phosphate and glucose 6-phosphate were up-regulated, indicating increased glucose utilization potentiated by lack of gut microbiota. Through querying the LINCS L1000 chemical database, Enrichr predicted that therapeutic drugs targeting the anti-inflammatory and ER stress pathways are potential remedies to mitigate PCB toxicity. In conclusion, our findings demonstrate that habitation of the gut microbiota drives PCBs-mediated hepatic responses, possibly due to crosstalk between gut and liver.
|Date made available