Aryl Hydrocarbon Receptor Activation by Persistent Organic Pollutants Impacts Gut Microbiota-Host Metabolic Homeostasis in Mice

BACKGROUND: Alteration of the gut microbiota through diet manipulation and environmental contaminants may disturb physiological homeostasis, leading to various diseases including obesity and type 2 diabetes. Since most exposure to environmentally-persistent organic pollutants (POPs) occurs through the diet, the host gastrointestinal tract and commensal gut microbiota are likely to be exposed to POPs. OBJECTIVES: We report that 2,3,7,8-tetrachlorodibenzofuran (TCDF), a persistent environmental contaminant, profoundly impacts the gut microbiota and host metabolism in an AHR-dependent manner. METHODS: Wild type and Ahr-/- male (6-week-old) C57BL/6J mice (5-6 per group) were treated with and without TCDF through the diet for five days at 24 µg/kg body weight. Combined 16S rRNA metagenomics, 1H nuclear magnetic resonance (NMR) metabolomics, targeted ultraperformance liquid chromatography coupled with triplequadrupole mass spectrometry (UPLC-TQMS) and biochemical assays were used. RESULTS: Dietary TCDF altered the gut microbiota by shifting the ratio of Firmicutes to Bacteroidetes. TCDF-treated mouse cecal contents were enriched with Butyrivibrio spp. , but depleted in Oscillobacter spp. in comparison with the vehicle-treated mice. These changes in the gut microbiota were associated with altered bile acid metabolism. Further, dietary TCDF inhibited the farnesoid X receptor (FXR) signaling pathway, and triggered significant inflammation and host metabolic disorders involving activation of bacterial fermentation, hepatic lipogenesis, gluconeogenesis and glycogenolysis, in an AHR-dependent manner. CONCLUSION: These findings provide new insights into the biochemical consequences of TCDF exposure involving the alteration of the gut microbiota, modulation of nuclear receptor signaling, and disruption of host metabolism.