The effect of deoxynivalenol on intestinal homeostasis studied by new approach methodologies

Summary

Mycotoxin deoxynivalenol (DON) is a fungal secondary metabolite that can contaminate cereal-based food. Human exposure to DON can lead to intestinal dysfunction. An intact and well-functioning intestinal barrier has a key role in maintaining bile acid homeostasis, which can be affected by intestinal DON exposure. This thesis provides novel insights into the hazards of DON exposure by showing its ability to induce intestinal inflammation and reduce bile acid reabsorption using in vitro intestinal models. Mechanism studies revealed that DON reduces bile acid reabsorption by inducing pro-inflammatory cytokines production and inhibiting protein synthesis, both of which are initiated by DON binding to the ribosomes which therefore was the molecular initiating event for bile acid malabsorption. In vitro data were extrapolated to human in vivo using physiologically based kinetic modeling facilitated reverse dosimetry. This allowed deriving a starting point for risk assessment of DON, minimizing the use of animal derived data.