ABSTRACT
The trichothecene toxin deoxynivalenol (DON) is a ribotoxic mycotoxin that contaminates cereal-based food. DON binds to ribosomes, thereby inhibiting protein translation and activating stress mitogen-activated protein kinases (MAPK). The activation of MAPK induces pro-inflammatory cytokine production. Emerging evidence showed that DON decreased bile acid reabsorption and apical sodium-dependent bile acid transporter (ASBT) expression in Caco-2 cell layers. We hypothesized that the effect of DON on decreased ASBT mRNA expression is regulated via pro-inflammatory cytokines. We observed that MAPK inhibitors prevented DON to induce IL-8 secretion and prevented the DON-induced downregulation of ASBT mRNA expression. However, DON-induced taurocholic acid (TCA) transport reduction was not prevent by the MAPK inhibitors. We next observed a similarity between the activity of the non-inflammatory ribotoxin cycloheximide and DON to decrease TCA transport, which is consistent with their common ability to inhibit protein synthesis. Together, our results suggest that DON-induced TCA malabsorption is regulated by MAPK activation-induced pro-inflammatory cytokine production and protein synthesis inhibition, both of which are initiated by DON binding to the ribosomes which therefore is the molecular initiating event for the adverse outcome of bile acid malabsorption. This study provides insights into the mechanism of ribotoxins-induced bile acid malabsorption in human intestine.
