Aflatoxin B₁ exposure disrupts the intestinal immune function via a soluble epoxide hydrolase-mediated manner

Aflatoxin B₁ (AFB₁) contamination in food and feed leads to severe global health problems. Acting as the frontier immunological barrier, the intestinal mucosa is constantly challenged by exposure to foodborne toxins such as AFB₁ via contaminated diets, but the detailed toxic mechanism and endogenous regulators of AFB₁ toxicity are still unclear. Here, we showed that AFB₁ disrupted intestinal immune function by suppressing macrophages, especially M2 macrophages, and antimicrobial peptide-secreting Paneth cells. Using an oxylipinomics approach, we identified that AFB₁ immunotoxicity is associated with decreased epoxy fatty acids, notably epoxyeicosatrienoic acids, and increased soluble epoxide hydrolase (sEH) levels in the intestine. Furthermore, sEH deficiency or inhibition rescued the AFB₁-compromised intestinal immunity by restoring M2 macrophages as well as Paneth cells and their-derived lysozyme and α-defensin-3 in mice. Altogether, our study demonstrates that AFB₁ exposure impairs intestinal immunity, at least in part, in a sEH-mediated way. Moreover, the present study supports the potential application of pharmacological intervention by inhibiting the sEH enzyme in alleviating intestinal immunotoxicity and associated complications caused by AFB₁ global contamination.