Polychlorinated biphenyls (
PCBs) are
persistent organic pollutants associated with
non-alcoholic fatty liver disease (
NAFLD). Previously, we demonstrated that the PCB mixture, Aroclor1260, exacerbated
NAFLD, reflective of toxicant-associated
steatohepatitis, in diet-induced obese mice, in part through pregnane-
xenobiotic receptor (PXR) and
constitutive androstane receptor (CAR) activation. Recent studies have also reported PCB-induced changes in the gut microbiome that consequently impact
NAFLD. Therefore, the objective of this study is to examine PCB effects on the gut-liver axis and characterize the role of CAR and PXR in microbiome alterations. C57Bl/6 (wildtype, WT), CAR and PXR knockout mice were fed a high fat diet and exposed to Aroclor1260 (20 mg/kg, oral gavage, 12 weeks). Metagenomics analysis of cecal samples revealed that CAR and/or PXR ablation increased bacterial alpha diversity regardless of exposure status. CAR and PXR ablation also increased bacterial composition (beta diversity) versus WT; Aroclor1260 altered beta diversity only in WT and CAR knockouts. Distinct changes in bacterial abundance at different taxonomic levels were observed between WT and knockout groups; however Aroclor1260 had modest effects on bacterial abundance within each genotype. Notably, both knockout groups displayed increased Actinobacteria and Verrucomicrobia abundance. In spite of improved bacterial diversity, the knockout groups however failed to show protection from PCB-induced hepato- and intestinal- toxicity including decreased
mRNA levels of ileal permeability markers (
occludin, claudin3). In summary, CAR and PXR ablation significantly altered gut microbiome in diet-induced
obesity while Aroclor1260 compromised intestinal integrity in knockout mice, implicating interactions between
PCBs and CAR, PXR on the gut-liver axis.