Evaluation of immunotoxic effects and metabolism of enniatins and beauvericin using in vitro models of the human intestinal epithelium

Enniatins (ENNs) and beauvericin (BEA) are mycotoxins produced by Fusarium species. They are frequently detected in cereal-based foods such as maize and wheat. Consequently, the gastrointestinal tract is a primary site of exposure for consumers of grain-containing foods. This study examined intestinal effects of four major ENNs: ENNB, ENNB1, ENNA, and ENNA1, and the structurally related mycotoxin BEA, using the primary human intestinal model EpiIntestinal (TM) tissues and a Caco-2/TH29-MTX-E12 co-culture. None of the compounds induced cytotoxicity or impaired the barrier integrity at concentrations ranging from 1 to 10 microM. Furthermore, all ENNs and BEA stimulated IL-6 secretion, with ENNA and ENNA1 inducing the strongest responses, while IL-8 secretion was only triggered by ENNA and ENNA1. Transport studies revealed that approximately 32% of ENNB and 25% of ENNB1 crossed from the apical to the basolateral side of the intestinal tissue within 4 h, whereas the other ENNs and BEA had transport ratios below 10%. Further findings suggested that uptake and intracellular accumulation of ENNs and BEA were influenced by their affinity to the efflux transporter P-glycoprotein (P-gp). In addition, several ENNB and ENNB1 metabolites were generated in the EpiIntestinal (TM) tissues and transported. Lastly, it was demonstrated that ENNB can disturb the metabolism of the sex hormone estradiol in human liver microsomes. Overall, ENNs and BEA showed limited acute toxicity in human intestinal models but elicited distinct inflammatory responses and differed in transport and metabolism. These findings may be of relevance when evaluating health risks from chronic, low-level dietary exposure