Investigation of the protective effects of probiotics and polyphenols on polychlorinated biphenyl-induced inflammation and oxidative stress: impact of biotransformation

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Background: Polychlorinated biphenyls (PCBs) are ubiquitous and persistent toxic pollutants. Diet is the primary route of human PCB exposure, which is associated with gastrointestinal and nervous system damage. PCB toxicity could be mediated by gut microbiota dysbiosis and mitochondrial dysfunction. PCB toxicity mediated via oxidative stress might be protected by polyphenols that can induce an antioxidant response via nuclear factor erythroid 2-related factor 2 (Nrf2). Probiotics could be protective via alteration of gut microbiota and anti-inflammatory effects.      Research Progress: We developed gut digestion model that simulates digestion of the gastrointestinal (GI) tract including colonic reactors containing human microbiota. We showed that human microbial catabolism of common dietary polyphenols led to differing polyphenol metabolite profiles and antioxidant capacities. Caco-2/HepG2 cell co-cultures were used to mimic human intestinal and hepatic first pass metabolism of the colonic digests. PCB-126 and PCB-153, dominant congeners in diet and human plasma, were subjected to the GI model. The impact of digests of PCBs in the presence and absence of polyphenols and/or probiotics are being studied on: (a) profiles of human gut microbiota and their metabolites; and (b) mitochondrial function and oxidative injury in human intestinal epithelial cells. Objectives: The overall objectives are to combine GI model digests with the first pass metabolism co-culture system to: (1) identify microbial and first pass metabolites generated from PCB exposure in the study of mechanisms of PCB-induced toxicity on human intestinal and neural cells; and (2) assess the effects of microbial and first pass metabolites of polyphenols and probiotics on PCB metabolism and toxicity with a focus on oxidative stress, inflammation and the Nrf2 signalling pathway. Experimental Design and Methodology: GI model digests of parent PCBs produced in the presence and absence of polyphenols and/or probiotics are subjected to the first pass Caco-2/HepG2 co-culture system. PCB, polyphenol and probiotic microbial metabolites are assessed via GC-MS, LC-MS and HPLC.Microbiome analysis will be analyzed by real-time qPCR using Illumina MiSeq. The first pass metabolites will be applied onto normal human neural progenitor cells co-cultured with a model for the human blood brain barrier to assess neuronal differentiation and viability. Mitochondrial function will be studied by the MitoPlate assay. Cytokines will be assessed by Luminex. Nrf2 levels will be studied via Western blot analysis. Gene expression analysis will use RT2 Profiler PCR Array.  Significance: This project will provide insight of PCB toxicity as affected by gut digestive and first pass metabolic processes with special reference to how inflammation, oxidative injury and mitochondrial dysfunction can be mediated by probiotic and polyphenol intervention.