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Prebiotic inulin consumption reduces dioxin-like PCB 126-mediated hepatotoxicity and gut dysbiosis in hyperlipidemic Ldlr deficient mice.

ABSTRACT: Exposure to some environmental pollutants increases the risk of developing inflammatory disorders such as steatosis and cardiometabolic diseases. Diets high in fermentable fibers such as inulin can modulate the gut microbiota and lessen the severity of pro-inflammatory diseases, especially in individuals with elevated circulating cholesterol. Thus, we aimed to test the hypothesis that hyperlipidemic mice fed a diet enriched with 8% inulin would be protected from the pro-inflammatory toxic effects of PCB 126. Four groups of male Ldlr^-/- mice were fed a high cholesterol diet containing 8% inulin or 8% cellulose (control) for 12 weeks. At weeks 2 and 4, mice were exposed to PCB 126 or vehicle (control). PCB 126 exposure induced wasting and impaired glucose tolerance, which were attenuated by inulin consumption. PCB 126 exposure induced hepatic lipid accumulation and increased inflammatory gene expression, which were both decreased by inulin consumption. In addition, inulin feeding decreased atherosclerotic lesion development in the aortic root and modulated the expression of enzymes related to glycolysis. Finally, 16S rRNA sequencing of gut microbial populations showed that PCB 126 modulated multiple microbiota genera (e.g., 3-fold decrease in Allobaculum and 3-fold increase in Coprococcus) which were normalized in inulin fed mice. Overall our data support the hypothesis that a dietary intervention that targets the gut microbiota may be an effective means of attenuating dioxin-like pollutant-mediated diseases.

SUBMITTER: Hoffman JB

PROVIDER: S-EPMC7220843 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Polychlorinated biphenyls (PCBs) are well known carcinogenic persistent environmental pollutants and endocrine disruptors. Our aim was to identify the possible dysregulation of genes in PCB exposed peripheral blood mononuclear cells (PBMCs) in order to give more insight into the differential pathophysiological effects of PCB congeners and mixtures, with an emphasis on immunological effects and oxidative stress. The PBMCs of a healthy volunteer (male, 56 years old) were exposed to a mixture of dioxin-like (DL)-PCBs (PCB 77, 81, 105, 114, 118, 123, 126, 156, 157, 167, 169, and 189, 250 µg/L resp.) or non-dioxin-like (NDL)-PCBs (PCB 28, 52, 101, 138, 153, 180, 250 µg/L resp.) or single PCB congener (no.28, 138, 153, 180, 250 µg/L resp.). After an incubation period of 24 h, a microarray gene expression screening was performed, and the results were compared to gene expression in control samples (PBMCs treated with the vehicle iso-octane). Treatment of PBMCs with the DL-PCB mixture resulted in the largest number of differentially regulated genes (181 upregulated genes >2-fold, 173 downregulated >2-fold). Treatment with the NDL-PCB mix resulted in 32 upregulated genes >2-fold and 12 downregulated genes >2-fold. A gene set enrichment analysis (GSEA) on DL-PCB treated PBMCs resulted in an upregulation of 125 gene sets and a downregulation of 76 gene sets. Predominantly downregulated gene sets were involved in immunological pathways (such as response to virus, innate immune response, defense response). An upregulation of pathways related to oxidative stress could be observed for all PCB congeners except PCB-28; the latter congener dysregulated the least number of genes. Our experiment augments the information known about immunological and cellular stress responses following DL- as well as NDL-PCB exposure and provides new information on PCB 28. Further studies should be performed to evaluate how disruption of these pathways contributes to the development of autoimmune diseases and cancer.

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Prebiotic inulin consumption reduces dioxin-like PCB 126-mediated hepatotoxicity and gut dysbiosis in hyperlipidemic Ldlr deficient mice.

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