Persistent organic pollutants modify gut microbiota–host metabolic homeostasis in mice through aryl hydrocarbon receptor activation

Background: Alteration of the gut microbiota through diet and environmental contaminants may disturb physiological homeostasis, leading to various diseases including obesity and type 2 diabetes. Because most exposure to environmentally persistent organic pollutants (POPs) occurs through the diet, the host gastro intestinal tract and commensal gut microbiota are likely to be exposed to POPs. oBjectives: We examined the effect of 2,3,7,8-tetrachloro dibenzofuran (TCDF), a persistent environmental contaminant, on gut microbiota and host metabolism, and we examined correlations between gut microbiota composition and signaling pathways. Methods: Six-week-old male wild-type and Ahr^–/– mice on the C57BL/6J background were treated with 24 μg/kg TCDF in the diet for 5 days. We used 16S rRNA gene sequencing,¹H nuclear magnetic resonance (NMR) metabolomics, targeted ultra-performance liquid chromatography coupled with triplequadrupole mass spectrometry, and biochemical assays to determine the microbiota compositions and the physiological and metabolic effects of TCDF. 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. compared with 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, triggered significant infammation and host metabolic disorders as a result of activation of bacterial fermentation, and altered hepatic lipo genesis, gluco neo genesis, and glyco genolysis 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.