4-Methylcatechol prevents deoxynivalenol-induced claudin-4 internalization and restores barrier integrity via Nrf2 activation.

Abstract

Deoxynivalenol (DON) is one of the most prevalent mycotoxins in food and animal feed and poses substantial risks to intestinal health. Although DON is known to impair epithelial barrier function, its molecular mechanisms remain incompletely defined. Nuclear factor erythroid 2-related factor 2 (Nrf2) has emerged as an important regulator in mycotoxin-induced barrier disruption. 4-Methylcatechol (4-MC), a microbial metabolite of dietary polyphenols, has been shown to activate Nrf2, but its ability to counteract DON toxicity has not been fully evaluated. This study investigated the protective effects of 4-MC against DON-induced intestinal barrier dysfunction in IPEC-J2 cells and weaned piglets, with emphasis on the Nrf2 pathway. Treatment with 4-MC induced a dose-dependent increase in the Nrf2 target gene NAD(P)H:quinone oxidoreductase 1 (NQO1) and enhanced claudin-4 expression at both mRNA and protein levels. Importantly, 4-MC reversed DON-mediated suppression of claudin-4 and prevented the loss of claudin-4 and ZO-1 from the cell membrane. Functionally, 4-MC restored transepithelial electrical resistance (TEER) and reduced DON-induced FITC-dextran permeability, indicating improved barrier integrity. These protective actions were abolished by brusatol, an Nrf2 inhibitor, confirming that Nrf2 activation is essential for the barrier-preserving effects of 4-MC. In the piglet model, DON exposure caused villus atrophy, fusion, and epithelial necrosis, whereas dietary 4-MC alleviated these histopathological lesions. Overall, the findings demonstrate that 4-MC significantly mitigates DON-induced intestinal epithelial damage through mechanisms largely dependent on Nrf2 activation, supporting its potential as a dietary strategy to protect intestinal health.

Key Findings

• 4-Methylcatechol (4-MC) activates Nrf2 and increases expression of the Nrf2 target gene NQO1.
• 4-MC reverses deoxynivalenol (DON)-induced suppression and internalization of claudin-4, preserving tight junction integrity.
• 4-MC restores intestinal barrier function as evidenced by improved transepithelial electrical resistance and reduced permeability, effects abolished by Nrf2 inhibition.
• In a piglet model, dietary 4-MC alleviates DON-induced intestinal histopathological damage such as villus atrophy and epithelial necrosis.

Clinical Significance

Citation

Li Enkai, Horn Nathan, Ajuwon Kolapo M. 4-Methylcatechol prevents deoxynivalenol-induced claudin-4 internalization and restores barrier integrity via Nrf2 activation. Toxicon : official journal of the International Society on Toxinology. 2026-Jun-15.