Polychlorinated biphenyls altered gut microbiome in CAR and PXR knockout mice exhibiting toxicant-associated steatohepatitis.
Toxicol Rep
; 8: 536-547, 2021.
Article
in En
| MEDLINE
| ID: mdl-33777700
ABSTRACT
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.
ACHS, anniston community healthy survey; AhR, arylhydrocarbon receptor; Aroclor1260; CAR, constitutive androstane receptor; Camp, cathelicidin anti-microbial peptide; Cdh5, adhesion molecule VE-cadherin; Cldn, claudin; Fasn, fatty acid synthase; Fgf15, fibroblast growth factor 15; Gut-liver; HFD, high fat diet; HOMA, homeostasis model assessment; IBD, inflammatory bowel diseases; LDA, linear discriminant analysis; LEfSe, linear discriminant analysis effect size; Microbiome; Muc, mucin; NAFLD; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; OTU, operational taxonomic unit; Ocln, occludin; PCBs; PCBs, polychlorinated biphenyls; PXR, pregnane-xenobiotic receptor; Pck1, phosphoenolpyruvate carboxykinase 1; Ppara, peroxisome-proliferator activated receptor alpha; RER, respiratory exchange rate; Reg3g, regenerating islet-derived protein 3-gamma; TASH; TASH, toxicant-associated steatohepatitis; Tff3, trefoil factor 3; Tjp1, tight junction protein 1; Tnfa, tumor necrosis factor; WT, wildtype
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Type of study:
Prognostic_studies
/
Risk_factors_studies
Language:
En
Journal:
Toxicol Rep
Year:
2021
Document type:
Article
Affiliation country:
United States