Deoxynivalenol (DON) is a type of mycotoxin that is disruptive to intestinal and immune systems. To better understand the molecular effects of DON exposure, we performed genome-wide comparisons of DNA methylation and gene expression from porcine intestinal epithelial cell IPEC-J2 upon DON exposure using reduced representation bisulfite sequencing and RNA-seq technologies. We characterized the methylation pattern changes and found 3030 differentially methylated regions. Moreover, 3226 genes showing differential expression were enriched in pathways of protein and nucleic acid synthesis and ribosome biogenesis. Integrative analysis identified 29 genes showing inverse correlations between promoter methylation and expression. Altered DNA methylation and expression of various genes suggested their roles and potential functional interactions upon DON exposure. Our data provided new insights into epigenetic and transcriptomic alterations of intestinal epithelial cells upon DON exposure and may advance the identification of biomarkers and drug targets for predicting and controlling the toxic effects of this common mycotoxin.
Inflammatory bowel disease (IBD) is a recurrent chronic inflammatory condition of the intestine without any efficient therapeutic regimens. Gut microbiota, which plays an instrumental role in the development and maturation of the immune system, has been implicated in the pathogenesis of IBD. Emerging evidence has established that early-life events particularly maternal influences and antibiotic treatment are strongly correlated with the health or susceptibility to disease of an individual in later life. Thus, it is proposed that there is a critical period in infancy, during which the environmental exposures bestow a long-term pathophysiological imprint. This notion sheds new light on the development of novel approaches for the treatment, i.e., early interventions, more precisely, the prevention of many uncurable chronic inflammatory diseases like IBD. In this review, we have integrated current evidence to describe the feasibility of the “able-to-be-regulated microbiota,” summarized the underlying mechanisms of the “microbiota-driven immune system education,” explored the optimal intervention time window, and discussed the potential of designing early-probiotic treatment as a new prevention strategy for IBD.
Background Deoxynivalenol (DON) is a major mycotoxin present in staple foods (particularly in cereal products), which induces intestinal inflammation and disrupts intestinal integrity. Lactoferrin (LF) is a multifunctional protein that contributes to maintaining intestinal homeostasis and improving host health. However, the protective effects of LF on DON-induced intestinal dysfunction remain unclear. Objectives This study aimed to investigate the effects of LF on the DON-induced intestinal dysfunction in mice, and its underlying protective mechanism. Methods Male BALB/c mice (5 wk old) with similar body weights were divided into 4 groups (n = 6/group) and treated as follows for 5 wk: Veh (peroral vehicle daily, commercial (C) diet); LF (peroral 10 mg LF/d, C diet); DON (Veh, C diet containing 12 mg DON/kg); and LF + DON (peroral 10 mg LF/d, DON diet). Intestinal morphology, tight junction proteins, cytokines, and microbial community were determined. Data were analyzed by two-way ANOVA or Kruskal-Wallis test. Results The DON group exhibited lower final body weight (−12%), jejunal villi height (−41%), jejunal occludin expression (−36%), and higher plasma interleukin (IL)-1β level (+85%) and jejunal Il1b mRNA expression (+98%) than the Veh group (P < 0.05). In contrast, final body weight (+19%), jejunal villi height (+49%), jejunal occludin (+53%), and intelectin 1 protein expression (+159%) were greater in LF + DON compared with DON (P < 0.05). Additionally, jejunal Il1b mRNA expression (−31%) and phosphorylation p38 and ERK1/2 (−40% and − 38%) were lower in LF + DON compared with DON (P < 0.05). Furthermore, relative abundance of Clostridium XIVa (+181%) and colonic butyrate levels (+53%) were greater in LF + DON compared with DON (P < 0.05). Conclusion Our study highlights a promising antimycotoxin approach of LF to alleviate DON-induced intestinal dysfunction via modulating the mitogen-activated protein kinase (MAPK) pathway and gut microbial community in mice.
Mycotoxin-induced liver injury is often accompanied by oxidative stress (OS) and inflammation. This research aimed to explore the potential mechanism of sodium butyrate (NaBu) in modulating hepatic anti-oxidation and anti-inflammation pathways in deoxynivalenol (DON)-exposed piglets. The results show that DON induced liver injury, increased mononuclear cell infiltration, and decreased serum total protein and albumin concentrations. Transcriptomic analysis revealed that reactive oxygen species (ROS) and TNF-α pathways were highly activated upon DON exposure. This is associated with disturbed antioxidant enzymes and increased inflammatory cytokines secretion. Importantly, NaBu effectively reversed the alterations caused by DON. Mechanistically, the ChIP-seq result revealed that NaBu strongly depressed DON-increased enrichment of histone mark H3K27ac at the genes involved in ROS and TNF-α-mediated pathways. Notably, we demonstrated that nuclear receptor NR4A2 was activated by DON and remarkably recovered with the treatment of NaBu. In addition, the enhanced NR4A2 transcriptional binding enrichments at the promoter regions of OS and inflammatory genes were hindered by NaBu in DON-exposed livers. Consistently, elevated H3K9ac and H3K27ac occupancies were also observed at the NR4A2 binding regions. Taken together, our results indicated that a natural antimycotic additive, NaBu, could mitigate hepatic OS and inflammatory responses, possibly via NR4A2-mediated histone acetylation.
Background & Aims: Disruption of lipid metabolism is largely linked to metabolic disorders, such as hypercholesterolemia (HCL) and liver steatosis. While cholesterol metabolic re-programmers can serve as targets for relevant interventions. Here we explored the dietary conjugated linoleic acids (CLA)-induced HCL in mice and the molecular regulation behind it.Methods: A high dose of CLA supplementation in the diet was used to induce HCL in mice and was found to cause a hyper-activated cholesterol biosynthesis programme in the liver, leading to cholesterol metabolism dysregulation. The effects of a small-molecule drug targeting PPARα, i.e., GW6471 were studied in vivo in mice fed diets with CLA supplementation for 28 days, and in primary hepatocytes derived from HCL-mice in vitro. Results:We demonstrate that CLA induced HCL and liver steatosis through multiple pathways. Among which was the PPARα-mediated cholesterogenesis. It was found to cooperate with SREBP2 via binding to Hmgcr and Dhcr7 (genes encoding key enzymes of the cholesterol biosynthetic pathway) and recruits the histone marks H3K27ac and H3K4me1 and cofactors. PPARα inhibition disrupts its physical association with SREBP2 by blocking cobinding of PPARα and SREBP2 to the genomic DNA response element. We showed that NR RORγ functions as an essential mediator that facilitates the interaction of PPARα and SREBP2 to modulate the cholesterol biosynthesis genes expression. Conclusions:Our study unravels that the small-molecule compound GW6471 exerts an attractive therapeutic effect for CLA-induced HCL, involving multiple pathways with the "PPARα-RORγ-SREBP2" being a potential complex player in this hepatic cholesterol biosynthesis programming.
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