Necroptosis contributes to the intestinal toxicity of deoxynivalenol and is mediated by methyltransferase SETDB1

Intestinal toxicity of deoxynivalenol (DON) has been widely described and apoptosis is generally considered to be the regulated cell death (RCD) mode of intestinal cells induced by DON. Necroptosis is a newly proposed RCD and has been proposed as a potential mechanism of intestinal disease. In this study, we found that chronic and acute DON exposure both caused morphological damage, digestive dysfunction, barrier breakdown, inflammation of the small intestine, and necroptosis of intestinal epithelial cells in piglets. Necroptosis was also detected when IPEC-1 cell damage was induced by DON in vitro. Upon the suppression of necroptosis in IPEC-1 cells by using inhibitors (Nec-1, GSK'872, or GW806742X), cell damage, epithelial barrier breakdown, oxidative stress and inflammatory response induced by DON were alleviated. Furthermore, pre-treatment with Nec-1 on piglets was also observed to protect the intestine against DON-induced enterotoxicity. Additionally, expression of histone methyltransferase SETDB1 was abnormally downregulated upon chronic and acute DON exposure in piglets. Further, necroptosis was activated in IPEC-1 cells due to knockout of SETDB1, confirming that down-regulation of SETDB1 activated the necroptosis of intestinal epithelial cells (IECs). Collectively, these results demonstrate that necroptosis of IECs is a mechanism of DON-induced enterotoxicity and SETDB1 mediates necroptosis upon DON exposure in IECs, suggesting the potential for targeted inhibition of necroptosis to alleviate mycotoxin-induced enterotoxicity and intestinal disease.