In today’s world, food safety is a critical concern that poses a significant risk to the health of individuals worldwide. Food is not limited to production, nutritious and healthy, but also safe food is essential. Food safety is affected by pollution factors, involving environment, microorganisms, physical, chemical, and processing pollution (Gizaw, 2019; Sánchez-Vallet et al., 2018). Mycotoxins are fungal secondary metabolites mainly found in crops, and they can contaminate plant-derived foods (Wei et al., 2022). The most common mycotoxins include deoxynivalenol (DON), fumonisin, aflatoxins, and zearalenone (Yang et al., 2020). Humans and animals are exposed to mycotoxins through the consumption of contaminated food (Hussein and Brasel, 2001). Study showed that global DON pollution in feed had exceeded 50% from 2004 to 2022, reaching 797 μg/kg in 2022 (DSM, 2022). It also found that DON contamination existed in cereal products and animal products such as meat, egg, and milk. Across 39 different dietary reports, people at different ages were exposed to 0.2–2.9 μg/kg body weight (BW) per day (Knutsen et al., 2017). DON is stable and could not be degraded during conventional food processing (Guo et al., 2020). After DON is absorbed by humans or animals, it will be quickly excreted in the urine, so the concentration of DON in urine is widely utilized as a biomarker of human DON exposure (Turner et al., 2008; Vidal et al., 2018). DON-exposed diets lead to the reduced feed intake and BW, and incalculable losses to animal husbandry (Holanda and Kim, 2021). It can affect early animal development, causing damage to multiple organs, and the disruption of gut microbiota (Jia et al., 2023). Many reports have demonstrated that the intestinal barrier function was affected by dietary exposure to DON, which include destruction of intestinal morphology, decrease in the abundance of proteins of tight junction, and inhibit intestinal cell proliferation (Liu et al., 2021; Ruhnau et al., 2021; Zhou et al., 2021). DON induces the accumulation of reactive oxygen species (ROS) in mitochondria (Tang et al., 2018), which can activate the mitogen-activated protein kinase signaling pathway and induce apoptosis and inflammation (Kang et al., 2019; Waśkiewicz et al., 2014).

As the essential line of defense against external stimuli, the intestinal epithelium is mainly composed of intestinal cells, including intestinal stem cells, paneth cells, goblet cells, and neuroendocrine cells (Mowat and Agace, 2014). Growing evidences show that when intestinal epithelial cells (IECs) are damaged, the intestinal barrier is damaged, and foreign bacteria enter the blood in large quantities, causing systemic diseases, such as alcohol-related liver disease, non-alcohol fatty liver disease, diabetes, cancer, arteriosclerosis, and chronic kidney disease (Albillos et al., 2020; Chen et al., 2019; Wang, 2021). When the intestines are challenged, innate immune cells such as dendritic cells (DCs), M cells, macrophages, mast cells, natural killer (NK) cells, and type 1, 2, and 3 innate lymphoid cells serve as the first line of defense (Agirman et al., 2021). Macrophages and dendritic cells are present throughout the gut lamina propria and contribute to innate and adaptive immunity to maintain gut homeostasis (Olivares-Villagómez and Van Kaer, 2018). IECs secrete cytokines colony-stimulating factor 1 (CSF-1), transforming growth factor-β (TGF-β), antimicrobial peptide, lysozyme, etc., which act on immune cells to resist external stimuli (Calabriso et al., 2022). CSF-1 is a critical cytokine that regulates the development, differentiation, and survival of macrophages and monocytes (Guilliams et al., 2020). It has a beneficial role in immune response and tissue repair and dysregulation of the signaling has been implicated in cancer progression (Buechler et al., 2021). Therefore, ensuring the regular growth and function of both the intestinal epithelial and immune cells are essential for promoting the overall well-being and health of both humans and animals.

Ferroptosis, an iron-dependent and non-apoptotic, is caused by metabolic dysfunction, subsequently leading to the damage to IECs as well as inflammatory injury (Tang et al., 2021; Xu et al., 2021). Recent studies have indicated that ferroptosis was involved in DON-induced intestinal and testicular damage (Liu et al., 2023; Yang et al., 2023). Selenium (Se) is an essential nutrient for humans and animals; because of the unique redox ability of Se and Se compounds, selenoproteins, it is mainly used for anti-cancer treatment, improving male reproductive capacity, and body immunity (Razaghi et al., 2021; Salas-Huetos et al., 2019; Zheng et al., 2019). Glutathione peroxidase 4 (GPX4), an antioxidant enzyme, is a critical feature of ferroptosis, which regulates cell death in ferroptosis by reducing lipid ROS levels (Yang et al., 2014). Se deficiency can impair the antioxidant system, leading to disruptions in energy metabolism and inflammation (Tang et al., 2022; Zhang et al., 2022). Supplementing with Se can effectively enhance GPX4 expression and inhibit ferroptosis-induced triggered by lipid peroxidation (Ingold et al., 2018; Wu et al., 2022a).

Studies have indicated that Se levels are reduced in patients with inflammatory bowel disease (Ye et al., 2021). Our previous studies have found that dietary Se deficiency significantly decrease the content of selenoprotein, reduce liver, cardiac, intestine and other multi-tissue organ damage (Tang et al., 2020; Tang et al., 2022; Zhang et al., 2021). Supplementing with Se can regulate intestinal immune response and effectively alleviate the occurrence of intestinal inflammation (Huang et al., 2021; Shi et al., 2021). Se has also been known to alleviate the deleterious effects of many toxic metals. Supplementing with Se can effectively inhibit the damage to the intestine, liver, and immune system of broilers and piglets caused by mycotoxin contamination in their feed (Chen et al., 2017; Hou et al., 2018; Li et al., 2020). Se supplementation has attenuated DON-induced chondrocyte cytotoxic damage and excessive procatabolic gene expression, thereby slowing the progression of Keshan disease (Wang et al., 2020a). Recent studies have shown that adding Se to the feed can alleviate the decrease in feed intake and intestinal barrier damage caused by DON damage (Van Le Thanh et al., 2016; Zhu et al., 2023). However, the mechanisms by which Se relieves DON-induced intestinal injury have yet to be fully refined.

IECs serve as the first line of defense against foreign infections in the intestine, and the proliferation and differentiation of these cells determine the integrity of the intestinal barrier. In this study, we revealed the mechanisms by which Se mitigates DON-induced intestinal damage using in vivo Se supplementation experiments. Further ferroptosis inhibitor experiments revealed that the PI3K/AKT-ferroptosis pathway is the main mechanism by which Se protects the intestines from DON-induced damage. Flow cytometry to analyze immune cell populations and employing MODE-K cells was used to investigate the generation mechanism of CSF-1, evaluating the interplay between epithelial cells and immune cells. This study provides an insight for further clarifying and improving our understanding of the mechanisms involved in Se as a mitigation strategy for mycotoxin-induced intestinal damage.