mTOR-Mediated Autophagy Regulates Fumonisin B₁-Induced Intestinal Inflammation via Pyroptosis In Vivo and In Vitro

Abstract

Fumonisin B 1 (FB 1 ) is a fungal metabolite, which has an incremental detection rate in grains and feed worldwide. The nucleotide-binding oligomerization domain-like pyrin domain containing protein 3 (NLRP3) inflammasome is a critical element in pyroptosis activation, which participates in regulating enteritis. Meanwhile, autophagy is also engaged in intestinal inflammation. However, the function of pyroptosis and autophagy in FB 1 -mediated enterotoxicity remains unclear. In this study, we explored the effects of FB 1 on enteritis and the underlying mechanism in vivo and in vitro. Our data showed that FB 1 exposure damaged the intestinal epithelium and promoted the secretion of inflammatory cytokines. Meanwhile, FB 1 exposure significantly upregulated the expression of pyroptosis-related genes. Then, MCC950, an inhibitor of NLRP3, significantly blocked FB 1 -induced pyroptosis in IPEC-J2 cells. In addition, FB 1 treatment elevated the levels of autophagy. Moreover, the phosphorylation of the mammalian target of rapamycin (mTOR), an upstream protein of the autophagy pathway, was inhibited by FB 1 exposure. Notably, rapamycin, an inhibitor of mTOR, instead of MHY1485, an agonist of mTOR, could ameliorate FB 1 -induced intestinal inflammatory injury and inhibit the upregulation of pyroptosis-related genes. In summary, we demonstrated that autophagy exhibited a protective effect against NLRP3 inflammasome-dependent pyroptosis on FB 1 -induced enteritis. Our data clarify a favorable protective role for the activation of autophagy in FB 1 poisoning.

Resveratrol alleviates fumonisin‐induced intestinal cytotoxicity by modulating apoptosis, tight junction, and inflammation in IPEC‐J2 porcine intestinal epithelial cells

“…32 Li et al found that FB1 induced intestinal epithelial barrier injury via endoplasmic reticulum stress. 33 via pyroptosis and mTOR-mediated autophagy was discovered by Mao et al 34 According to earlier study, FB1 has a considerable impact on the gut microbiota and the relative abundance of bacteria at the phylum to species level, with Firmicutes and Proteobacteria being the two major groups that are differentially affected. 21 In addition, fumonisin exposure has caused serious harm to humans and animals, resulting in significant economic losses.…”

Mild endoplasmic reticulum stress alleviates FB1-triggered intestinal pyroptosis via the Sec62-PERK pathway

“…After collecting the intestinal tissue samples, pathological tissue sections were made (H&E). For the details see Mao et al (Mao et al 2022 ).…”

“…After FB1 treatment, cells were washed twice with pre-cooled PBS. Then, the qRT-PCR detail steps were reported in our previous study (Mao et al 2022 ). The primers used are shown in Table 1 .…”

“…Subsequent steps are the same as the above-mentioned 12-well plate treatment of cells. For the following steps, see Mao et al's study (Mao et al 2022 ).…”

Insights into the intestinal toxicity of foodborne mycotoxins through gut microbiota: A comprehensive review

“…(2020) demonstrated that DON activates autophagy in IPEC‐J2 cells by disrupting the Phosphoinositide 3 kinase (PI3K)–Protein Kinase B (Akt)–mTOR signaling pathway, resulting in cytotoxicity and apoptosis. Both in vivo and in vitro experiments have provided substantial evidence that FB 1 exposure triggers mTOR‐mediated autophagy, promoting intestinal cell charring and inflammation (Mao et al., 2022). Additionally, OTA exposure has been found to activate autophagy in IPEC‐J2 cells through the Extracellular regulated protein kinases 1/2 (ERK1/2) cascade (Wang, Li, Chen, et al., 2018).…”