Do trichothecene mycotoxins disrupt intestinal barrier integrity?

Exposure to trichothecene mycotoxins, such as nivalenol and macrocyclic trichothecenes (including roridin and verrucarin), significantly compromises the intestinal epithelial barrier. This disruption proceeds through a highly coordinated intracellular cascade that impacts cellular translation and structural integrity.

Mechanistic pathways

• Ribosomal translation arrest: These mycotoxins non-covalently bind to the peptidyl transferase center at the active A-site of the eukaryotic 60S ribosomal subunit. This binding physically blocks peptide bond formation, halts translation elongation, and causes global inhibition of protein synthesis.
• Ribotoxic stress response: The resulting translation arrest and ribosomal stress directly trigger the phosphorylation and activation of stress-activated mitogen-activated protein kinase (MAPK) signaling pathways, specifically p38, JNK, and ERK.

Impact on epithelial integrity

• Tight junction degradation: Because cellular translation is restricted, the de novo synthesis of structural proteins required to maintain the epithelial barrier is suppressed. This results in the down-regulation and mislocalization of essential tight junction proteins, including claudin-3, claudin-4, occludin, and zonula occludens-1 (ZO-1).
• MAPK-mediated disruption: Simultaneously, active MAPK signaling downstream of ribosomal stress regulates tight junction assembly, accelerating the disassembly and degradation of these structural complexes.
• Increased permeability: The loss and disorganization of tight junction proteins weaken paracellular seals. This structural failure causes a marked decrease in transepithelial electrical resistance (TEER) and a substantial increase in paracellular permeability to macromolecules.

Bottom line

• Trichothecene mycotoxins disrupt intestinal barrier integrity through a clear class-wide cascade: ribosomal inhibition and MAPK-activated ribotoxic stress down-regulate and mislocalize key tight junction proteins (claudins, occludin, and ZO-1), ultimately driving a decrease in transepithelial electrical resistance and a severe increase in paracellular permeability.