Gut Microbiome Critically Impacts PCB-induced Changes in Metabolic Fingerprints and the Hepatic Transcriptome in Mice
Year: 2020
Type: article
Abstract: Polychlorinated biphenyls (PCBs) are ubiquitously detected and have been linked to metabolic diseases. Gut microbiome is recognized as a critical regulator of disease susceptibility; however, little is known how PCBs and gut microbiome interact to modulate hepatic xenobiotic and intermediary metabolism. We hypothesized the gut microbiome regulates PCB-mediated changes in the metabolic fingerprints and hepatic transcriptome. Ninety-day-old female conventional and germ-free mice were orally exposed to the 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. RNA-seq was conducted in liver, and endogenous metabolites were measured in liver and serum by LC-MS. Prototypical target genes of aryl hydrocarbon receptor, pregnane X receptor, and constitutive androstane receptor were more readily upregulated by PCBs in conventional conditions, indicating PCBs, to the hepatic transcriptome, act partly through the gut microbiome. In a gut microbiome-dependent manner, xenobiotic, and steroid metabolism pathways were upregulated, whereas response to misfolded proteins-related pathways was downregulated by PCBs. At the high PCB dose, NADP, and arginine appear to interact with drug-metabolizing enzymes (ie, Cyp1-3 family), which are highly correlated with Ruminiclostridium and Roseburia, providing a novel explanation of gut-liver interaction from PCB-exposure. Utilizing the Library of Integrated Network-based Cellular Signatures L1000 database, therapeutics targeting anti-inflammatory and endoplasmic reticulum stress pathways are predicted to be remedies that can mitigate PCB toxicity. Our findings demonstrate that habitation of the gut microbiota drives PCB-mediated hepatic responses. Our study adds knowledge of physiological response differences from PCB exposure and considerations for further investigations for gut microbiome-dependent therapeutics.
Source: Toxicological Sciences
Language: English
Topic: Gut microbiota and health
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: Epigenetic Regulation of Drug Metabolism by Developmental Exposure to PBDEs, Developmental Regulation of Drug Metabolism by Targeting the Gut Microbiome, Intellectual and Developmental Disabilities Research Center, Environmental Pathology/Toxicology Training Program, PCB-mediated dysbiosis of the gut microbiome: A missing link in PCB-mediated neurodevelopmental disorders?, G9000060683, Iowa Superfund Research Program: Airborne PCBs: Sources, Exposures, Toxicities, Remediation, G9000325323, Environmental Health Sciences Research Center, University of Washington Interdisciplinary Center for Exposures, Diseases, Genomics & Environment, Developmental flame retardant exposure, gut microbiome, and obesity
OpenAlex ID: W3034666419