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. 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 aryl hydrocarbon receptor (AHR)-dependent manner.
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 five days. 16S rRNA gene sequencing, 1H
nuclear magnetic resonance (NMR) metabolomics, targeted
ultra-performance liquid chromatography coupled with triplequadrupole
mass spectrometry (UPLC-TQMS) and biochemical assays were used 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. in comparison 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, and triggered significant inflammation and host
metabolic disorders as a result of activation of bacterial
fermentation, and altering 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.